Cell culturing system for cultivating adherent cells and liquid supply interface comprising a cell culture container

ABSTRACT

The invention relates to a liquid supply interface ( 62, 62′, 62″, 62 ′″) for a cell culture system for supplying cell cultures found in different cell culture containers ( 10, 10′, 10 ″) with a nutrient medium, wherein the liquid supply interface ( 62, 62′, 62″, 62 ′″) comprises: a housing ( 68 ) defining a flow area ( 72 ); a first connection formation ( 76 ) for the liquid-transferring connection of a first fluid line ( 84 ) to the housing ( 68 ); a second connection formation ( 78 ) formed separately from the first for the liquid-transferring connection of a second fluid line ( 88 ) to the housing ( 68 ); a third connection formation ( 80 ) formed separately from the first two for the liquid-transferring connection of the housing ( 68 ) to a third fluid line; a coupling formation ( 64, 66 ) formed separately from the connection formations ( 76, 78, 80 ), which is formed for the producible and detachable liquid-transferring coupling contact according to the operation, with a corresponding counter-coupling formation ( 38, 40 ) of a cell culture container ( 10, 10′, 10 ″).

The present invention relates to improvements in cell culturing systemscomprising at least one cell culture container for collection andsupply, i.e. particularly for cultivating with the goal of propagation,of adherent cells therein, comprising a nutrient medium reservoir forsupplying the adherent cells in the cell culture container withnutrients, having a cleaning fluid reservoir for cleaning fluid flowpaths or/and flow areas with the cleaning fluid, and comprising a liquidsupply interface for coupling to the cell culture container.

The present application further relates particularly to theaforementioned liquid supply interface for a cell culture system forsupplying cell cultures present in different cell culture containershaving a nutrient medium. The present application further relates tocell culture containers, which are formed for provisionalfluid-mechanical coupling with the liquid supply interface in order tointroduce fresh nutrient medium into the cell culture container and toremove normally used or at least old nutrient medium from the cellculture container, once the liquid supply interface is coupled to a cellculture container in a fluid-mechanical manner.

Bioreactors specialized for their respective task and that aretechnically very complex have previously been used in the prior art forcultivating cells, which typically have a reactor area that can beheated by a heating mechanism integrated into the bioreactor and thecontent of which can be stirred or thoroughly mixed by a stirringmechanism permanently installed on the bioreactor.

A nutrient medium reservoir is typically provided on such types ofbioreactors, which is permanently connected to the reactor area vialines as the core of cell cultivation. An additional line can go fromthe reactor to a discharge or a disposal collection container. This lineis also typically permanently connected to the reactor area. Thus, thereis a 1:1 relationship between the number of reactor areas and the numberof nutrient medium reservoirs.

When cultivating adherent cells, often disposable cell culturecontainers are used in the prior art, which are typically produced fromtransparent plastic so as to observe the cultivated cells and arecompletely passive, i.e. are formed without function units influencingthe container area thermally (heating/cooling) or mechanically(stirring). To the extent that such type of disposable cell culturecontainer requires a predetermined temperature control, this must occurin an incubator formed for this purpose or a similar device. A mixing ofthe liquid collected in the container area of such type of disposablecell culture container cannot be achieved with the disposable cellculture container in the absence of an agitator mechanism or optimallyby a shaking the container.

The disposable cell culture containers in the prior art typically have aneck connecting piece equipped with an outer thread as the single accessopening, which can be closed with a screw cap in the conventionalmanner. The disposable cell culture container can be filled, emptied,and even ventilated as desired through the neck connecting piece

The disadvantage with the aforementioned bioreactors in a cell culturesystem is their high level of specialization for predeterminedapplication cases, which means that it may be necessary to maintaindifferent bioreactors even when cultivating merely a few different cellcultures.

After a single use of a bioreactor, in order to prevent contaminationfrom cultures processed subsequently, the necessary cleaning effort forsubsequent usage is either very extensive or the bioreactor will have tobe taken out of operation and disposed of after a single use despite itsrelatively high procurement costs. Both scenarios increase significantlythe costs associated with cell cultivation in such type of bioreactor.

When using the aforementioned disposable cell culture containers, theprocurement and operating costs associated with them are significantlylower compared with the previously discussed bioreactors. However, suchtype of disposable cell culture containers often have a usable volume ofless than 1 L and thus are only set up for manual operation on alaboratory scale, which keeps the yields achievable with said disposablecell culture containers undesirably low. Because of the single availableaccess opening, which can be closed off with a screw top, the knowndisposable cell culture containers are not suitable for automation andthus, for use for culturing cells on an industrial scale.

Therefore, the object of the present invention is to overcome theaforementioned disadvantages of the prior art in cultivating adherentcells and to indicate technical teaching, which enables the cultivationof adherent cells with comparatively low costs (the reference variablein this case should be the costs per unit of weight of cell materialobtained) and relatively higher yields.

This object is attained by the present invention by means of three mainaspects, which are connected via a common inventive idea and whichinteract with one another, and different aspects relate to one and thesame cell culture system.

According to a first aspect of the present invention, the aforementionedobject is attained by a liquid supply interface for a cell culturesystem for supplying cell cultures found in different cell culturecontainers with a nutrient medium, in which the liquid supply interfaceaccording to the invention comprises the following:

a housing defining a flow area;a first connection formation for the liquid-transferring connection of afirst fluid line to the housing;a second connection formation formed separately from the first for theliquid-transferring connection of a second fluid line with the housing;a third connection formation formed separately from the first two forthe liquid-transferring connection of the housing with a third fluidline;a coupling formation formed separately from the connection formations,which is formed for the producible and detachable liquid-transferringcoupling contact according to the operation, with a correspondingcounter-coupling formation of a cell culture container;a first liquid flow path, which extends between the flow area and thefirst connection formation for introducing a first liquid from theoutside into the flow area;a second liquid flow path, which extends between the flow area and thesecond connection formation for introducing a second liquid differentfrom the first from the outside into the flow area; a third liquid flowpath, which extends between the flow area and the third connectionformation for removing a liquid from the flow area; anda coupling flow path, which extends between the flow area and thecoupling formation in order to remove a liquid from the flow area and/orto introduce it to said flow area via the coupling formation, in whichthe first, the second, and the third liquid flow path each have a valveconfiguration, which is completely surrounded—with the exception of therespective liquid flow path—by the housing, incorporated in it, withouta continuous signal- or/and power-transferring physical connectionsurrounded by the valve configuration up to the outside of the housing;in which a control configuration with a signaling means generating anelectric or/and magnetic or/and electromagnetic field is allocated toeach valve configuration, the field of which acts upon a correspondinglyfield-sensitive counter signaling means of the valve configurationwithout contact, in which each valve configuration can be switchedbetween a blocked position, in which the valve configuration interruptsa liquid flow in the liquid flow path in which it is arranged, and anoutlet position in which the valve configuration enables a liquid flow,by means of the field acting upon its counter-signaling means.

The aforementioned connection formations makes it possible to introduceliquids into the housing of the liquid supply interface and thus intothe flow area and to remove it from said area. These liquids may be, forexample, a nutrient medium and a cleaning fluid. Furthermore, fluid maybe removed from the housing via one of the connection formations, i.e.from the flow area defined in the housing.

The liquid supply interface can be coupled with a cell culture containerin a liquid-transferring manner with the at least one couplingformation. Thus, it is possible to place one and the same liquid supplyinterface in coupling contact one after the other with one of aplurality of cell culture containers in a liquid-transferring manner andthereby obtain the possibility of introducing liquid from the flow areaof the liquid supply interface into the respectively coupled cellculture container or to remove it from said container into the flow areaof the liquid supply interface. For example, used nutrient medium ornutrient medium that is no longer fresh can be transferred from acoupled cell culture container in a liquid-transferring manner to thecoupling formation and placed in the flow area via the coupling flowpath and routed from said flow area through the aforementioned thirdliquid flow path from the flow area through the third connectionformation out to a discharge or a collection container.

Due to the three connection formations formed separately from oneanother, as is explained in detail in the following, the requirementthat the liquid supply interface be in contact with different cellculture containers is met without the risk of a cell culture containerbeing cross-contaminated with contaminated contents from a cell culturecontainer coupled downstream. Because, for example, nutrient medium froma nutrient medium reservoir can be introduced into the flow area via thefirst liquid flow path by means of the first connection formation andfrom the flow area then further routed into a cell culture containerconnected in a liquid-transferring manner via the coupling flow path.The corresponding valve configurations can be switched between theblocked position and the outlet position without mechanical access to avalve body or/and valve seat of the valve configuration being necessarythrough the control configuration in a contactless manner via thefield-generating signaling means.

As previously mentioned, desired nutrient medium can likewise no longerbe routed through the coupling formation along the coupling flow pathwithin the cell culture container into the flow area and diverted fromthe flow area to a discharge or collection container via the thirdliquid flow path.

Due to the provision of the second connection formation with the secondliquid flow path formed there, a cleaning fluid, for example, can beintroduced from a cleaning fluid reservoir connected to the secondconnection formation in a liquid-transferring manner into the flow areaand removed from said area via the third liquid flow path. Thus, theflow area can be rinsed clean by the cleaning fluid in that the cleaningfluid flows from the second connection formation to the third connectionformation through the flow area.

Due to the suitable positioning of the first, second, and thirdconnection formation, it is possible to ensure that the cleaning rinsingcovers all liquid flow paths, primarily those that are necessary forintroducing fresh nutrient media into the cell culture container.

The introduction of fresh nutrient medium into a cell culture containercoupled to the coupling formation is critical for undesirablecross-contamination when supplying different cell culture containers viaone and the same liquid supply interface, because contaminated materialcan only reach a previously clean cell culture container via thecoupling flow path. The removal of nutrient medium from cell culturecontainers, on the other hand, is not critical as long as the nutrientmedium removed from a cell culture container is only being disposed ofor will only be retained separately.

As previously referenced, the valve configurations may be switchedadvantageously in a contactless manner between the blocked position andthe outlet position by a field-generated signaling means, whichinteracts with a correspondingly field-sensitive counter-signaling meansof the valve configuration. Thus, the valve configuration can behermetically sealed from the environment. The valve configurations orcomponents themselves therefore only come into contact with liquids thatcan flow along their respective liquid flow paths. Contamination ofvalve configurations from the exterior is prevented by the switching bymeans of field-generating signaling means and correspondinglyfield-sensitive counter-signaling means if there is no exteriorconnection, on the other hand.

If it is revealed in this application that a valve configuration isincorporated in the housing without a continuous signal- or/andenergy-transferring physical connection from the valve configuration upto the exterior of the housing, then this case includes mechanicalsignal- or/and energy-transferring through rod linkage or/and gearbox,screw or spindle drives, and the like, with which a valve body of thevalve configuration can be lifted up from its valve seat from outside ofthe housing and can be set back down on it. The phrase continuoussignal- or/and energy-transferring physical connection also includeswires running from the exterior of the housing to the valveconfiguration or a valve drive, with which electrical power can berouted to an electric drive, with which, in turn, a valve body of thevalve configuration can be driven in order to generate movement betweenthe blocked position and the outlet position.

In order to prevent any influence from the outside on the valveconfigurations of the connection formations, each valve configurationwith valve seat and valve body should therefore be completely surroundedby the housing, without said surrounding being interrupted by a physicalsignal- or/and energy-transferring connection. The single exception tothe complete surrounding of the valve configuration by the housing arethe liquid flow paths allocated to the valve configurations, which mustremain free of housing material in order to enable the flow of liquidalong the respective liquid flow path.

Due to a corresponding switching of the control configuration, the valveconfigurations of the liquid supply interface may be switched, forexample, such that initially after establishment of aliquid-transferring coupling contact of the coupling formation with thecorresponding counter-coupling formation of a cell culture container,the flow area is flushed with cleaning fluid via the second and thethird liquid flow path. Thereby, any valve configurations at thecorresponding counter-coupling formation of the cell culture containercan also be cleaned.

Following this, nutrient medium can be removed from the cell culturecontainer via the coupling flow path and the third liquid flow path.Subsequently, there can be another flushing of the flow area of theliquid supply interface with cleaning fluid via the second and the thirdliquid flow path thereby effecting renewed cleaning of the flow area.

Following this, there may be an additional cleaning rinse with freshnutrient medium via the first and the third liquid flow path of the flowarea of the liquid supply interface in order to remove any residue ofcleaning fluid from the liquid supply interface.

After this, fresh nutrient medium may be introduced to the respectivelycoupled cell culture container via the first liquid flow path and thecoupling flow path.

Subsequently, the cell culture container now freshly supplied withnutrient medium can be uncoupled from the liquid supply interface,possibly after an additional cleaning rinse with cleaning fluid via thesecond and the third liquid flow area, and connected to another cellculture container. The aforementioned rinsing and introduction andremoval measures can then be repeated. This can be repeated for anynumber of cell culture containers, so that an n:1 number relationshipcan be realized between a plurality of cell culture containers and onenutrient medium reservoir.

Essentially, however, it is also possible to introduce only freshnutrient medium into one cell culture container into only remove thenutrient medium existing there from the cell culture container. What isdecisive is that the liquid supply interface between aliquid-transferring coupling contact with different cell culturecontainers can be flushed and cleaned with cleaning fluid in sufficientmeasure by the corresponding flush procedures in order to prevent therisk of cross-contamination that can occur during coupling one and thesame liquid supply interface to different cell culture containers.

To facilitate the maximum effective cleaning of the flow area of theliquid supply interface, a provision according to an advantageousfurther embodiment of the present invention is that the flow area extendessentially in a straight line at least between the connectionformation, which is formed for connecting the liquid supply interfacewith a cleaning fluid reservoir—which is preferably the secondconnection formation—and the connection formation, which is formed forconnecting the liquid supply interface with a discharge or disposalcontainer or the like—which is preferably the third connectionformation. In order to prevent intermeshing areas, the flow area ispreferably formed essentially circular-cylindrically. Thecircular-cylindrical formation may, however, deviate from an idealcircular-cylindrical shape in those areas in which the first, thesecond, or the third liquid flow path or the coupling flow path feedsinto the flow area.

In order to expand the functional scope of the liquid supply interfacediscussed here to include the option of removing samples of media from acell culture container, in addition to the previously mentionedfunctions, it may be provided according to a further embodiment of thepresent invention that the liquid supply interface further comprise thefollowing:

a fourth connection formation formed separately from the remaining threefor the liquid-transferring connection of the housing to a fourth fluidline anda fourth liquid flow path, which extends from the flow area between theflow area and the fourth connection formation for removing a liquid.

The fourth liquid flow path can, for example, lead to a samplecollection container or a sample collection outlet, at which the mediasample removed from the cell culture container is collected for furtherprocessing. Through such type of sample collection, it can bedetermined, for example, by means of chemical analysis of the nutrientmedium removed from a cell culture container, whether the nutrientmedium is sufficiently pure enough, the cultivated cell cultures havethe life cycles as expected, and so on and so forth.

The fourth liquid flow path preferably also has a valve configurationthe same as the first, the second, and the third liquid flow path. Toavoid unnecessary repetitions, reference is hereby made to the previousand the following description of the valve configuration of the first,the second, and the third liquid flow path, which also applies to thevalve configuration of the fourth liquid flow path, regarding theembodiment of the valve configuration of the fourth liquid flow path andthe associated technical advantages.

One or more of the first to fourth connection formation may be formed asa detachable connection formation to which a fluid line is connectableto the housing of the liquid supply interface in a detachable manner,for example through detachable plug connections, as are known in theprior art. This may be helpful when different fluid lines are to beconnected to one or more connection formations in a liquid-transferringmanner at different times. This is, however, not the case with thepreferred use of the liquid supply interface discussed here for a cellculture system for supplying different cell culture containers withnutrient medium. For reasons of increased operational safety andprimarily for the improvement of hygiene, it is therefore preferable toform each of the first to fourth connection formations as a permanentconnection formation, to which first to fourth fluid lines arepermanently connected to the housing of the liquid supply interface in aliquid-transferring manner, according to the operation. For example,such type of connection formations can be implemented through screwconnections, optionally with the intermediate configuration of sealingmeans, of connection formation and fluid line or through bonding,welding, soldering, or so on and so forth.

The phrase “permanently connected in a liquid-transferring manneraccording to the operation” in this case means that, except for a caseof damage or maintenance, once a fluid line is connected with aconnection formation, it is not again detached during the conventionaloperation service life of a liquid supply interface. This is contrary tothe coupling formation, which is precisely formed according to theoperation frequently coupled to a counter-coupling formation of a cellculture container in a liquid-transferring manner and will be againdetached from it.

A further increase in the hygiene that can be achieved in the liquidsupply interface of the present application can take place by providingmultiple coupling formations and by separating the function thereof.Thus, the previously discussed coupling formation may, for example, be afirst coupling formation through which, for example, exclusively freshnutrient medium is introduced in a cell culture container coupledthereto during operation of the liquid supply interface. Furthermore,the liquid supply interface may have a second coupling formation formedseparately from said first coupling formation, through which, forexample, exclusively nutrient medium is removed from a coupled cellculture container when the coupling contact is established.

In general, in order to improve hygiene according to an advantageousfurther embodiment of the present invention, the aforementioned couplingformation may have a first coupling formation, the liquid supplyinterface may have a second coupling formation formed separately fromthe first, which is formed for coupling contact that is producibleaccording to the operation and detachable in a liquid-transferringmanner with a corresponding second counter-coupling formation of thecell culture container, and the liquid supply interface then may have asecond coupling flow path, which extends between the flow area and thesecond coupling formation, in order to remove liquid from the flow areaor/and to introduce it to said area via the second coupling formation.

The aforementioned advantageous functional separation of the twocoupling formations of a further-embodied liquid supply interface aspreviously advantageously described can thereby be even further improvedwith respect to the achievable hygiene standard in that the liquidsupply interface has a connection flow path extending between the firstand the second coupling formation and the liquid supply interface insaid path has a separating valve configuration, which is completelysurrounded by the housing and incorporated in it, without a continuoussignal- or/and power-transferring physical connection from theseparating valve configuration up to the exterior of the housing—withthe exception of the connection flow path, in which a controlconfiguration with a signaling means generating an electric or/andmagnetic or/and electromagnetic field is allocated to the separatingvalve configuration, the field of which acts upon a correspondinglyfield-sensitive counter-signaling means of the separating valveconfiguration without contact, in which the separating valveconfiguration can be switched between a blocked position, in which theseparating valve configuration interrupts a liquid flow in theconnecting flow path, and an outlet position, in which the separatingvalve configuration enables a liquid flow by means of the field, actingupon its counter-signaling means. The introduction of nutrient mediuminto a coupled cell culture container and the removal of nutrient mediumfrom said container can be completely functionally and spatiallydecoupled from one another in a fluid-mechanical manner through theseparating valve configuration. With the corresponding switching of theseparating valve configuration, the flow area of the liquid supplyinterface can thus be subdivided into two sub-flow areas, in whichexclusively cleaning fluid and fresh nutrient medium can flow throughone sub-flow area and used nutrient medium and cleaning fluid and whenthe cleaning fluid is rinsed out, also fresh nutrient medium, can flowthrough the other sub-flow area, out of the cell culture container, uponcorresponding activation of the separating valve configuration. Thus, amalfunction in the supply of the cell culture containers with freshnutrient medium through contamination with previously discharged usednutrient medium from another previously coupled cell culture containercan be avoided.

In order to clean the flow area, the separating valve configuration canbe activated in its outlet position such that liquid can flow throughfor cleaning and also for subsequent rinsing of cleaning fluid throughfresh nutrient medium of the entire flow area of cleaning fluid or/andfresh nutrient medium.

To prevent undesirable bypass malfunctions, it is advantageous if theconnection flow path is the only liquid flow path extending between thefirst and a second coupling formation. This will also serve to preventundesirable cross-contamination of cell culture containers coupledchronologically one after the other.

A suitable functional separation of the two coupling formations and thecoupling flow paths allocated to them can be further supported in thatthe separating valve configuration is arranged such that the first andthe second liquid flow path can be separated from the second couplingthe flow path but not from a first coupling flow path by theconfiguration, and that the third liquid flow path can be separated fromthe first coupling flow path but not from the second coupling flow pathby the configuration. In this case, each sub-flow area has a couplingflow path and at least one liquid flow path, and a coupling formationand at least one connection formation is connected to each sub-flow areain a liquid-transferring manner.

More precisely, preferably the first and the second liquid flow pathfeed into one sub-flow area and the third liquid flow path feeds intothe respectively other sub-flow area.

Then, if the aforementioned configuration of the liquid flow pathsand/or the connection formations allocated to them is maintained, i.e.introduction of fresh nutrient medium into the flow area via the firstcoupling flow path, introduction of a cleaning fluid into the flow areavia the second liquid flow path, and discharge of liquids from the flowarea via the third liquid flow path for example, the one sub-flow areacan be used for introducing fresh nutrient medium into a coupled cellculture container and the respective other sub-flow area can be used todischarge used nutrient medium from the coupled cell culture container,in which these two functions are advantageously hygienically separatedfrom one another due to the separating valve configuration.

Then, if the previously mentioned fourth connection formation is formedwith a fourth liquid flow path at the liquid supply interface, thefourth liquid flow path advantageously feeds into the same sub-flow areaas the third liquid flow path provided for discharging liquid from theflow area. This enables symmetrical distribution of liquid flow pathsand coupling flow paths in the two sub-flow areas formed by theseparating valve configuration.

Because the possibility of contaminating the discharging liquid flowpath, for example through metabolism of products in these cell cultureswithin the cell culture container, is greater than with the liquid flowpaths starting from a reservoir with fresh liquid (for example nutrientmedium or/and cleaning fluid) when discharging fluid from a cell culturecontainer coupled to the liquid supply interface, it can beadvantageous, when a separate option for removing media samples from acoupled cell culture container is desired, to provide separate couplingflow paths for removing media samples from one cell culture container,on one hand, and for merely disposing of used nutrient medium, on theother hand.

Accordingly, there may be a design option according to a furtherembodiment of the present invention for implementing thishygiene-increasing measure such that the liquid supply interface has athird coupling formation formed separately from the first and the secondand a third coupling flow path, which extends between the flow area andthe third coupling formation, in order to discharge liquid from the flowarea or/and to introduce liquid into said area via the third couplingformation, in which the third coupling formation is formed for couplingcontact that is producible according to the operation and detachable ina liquid-transferring manner with a corresponding third counter-couplingformation of the cell culture container.

In turn, it may be advantageous from the previously mentionedconsiderations for improving the hygiene achievable with the liquidsupply interface to design the individual coupling formations to beseparable from one another in a fluid-mechanical manner by theseparating valve configurations. To this end, it may be providedaccording to a further embodiment of the prevent invention that theaforementioned connection flow path be a first connection flow path andthat the aforementioned separating valve configuration be a firstseparating valve configuration and that the liquid supply interface havea second connection flow path extending between the second and the thirdcoupling formation and the liquid supply interface in said path have aseparating valve configuration separate from the first, which iscompletely surrounded by the housing and incorporated in it, without acontinuous signal- or/and power-transferring physical connection fromthe second separating valve configuration up to the exterior of thehousing—with the exception of the connection flow path,

in which a control configuration with a signaling means generating anelectric or/and magnetic or/and electromagnetic field is allocated tothe second separating valve configuration, the field of which acts upona correspondingly field-sensitive counter-signaling means of the secondseparating valve configuration without contact, in which the secondseparating valve configuration can be switched between a blockedposition, in which the second separating valve configuration interruptsa liquid flow in the second connecting flow path, and an outletposition, in which the second separating valve configuration enables aliquid flow, by means of the field, acting upon its counter-signalingmeans.

The separating valve configurations are preferably identically formedwith the aforementioned valve configurations of the connectionformations. This facilitates production and assembly of the liquidsupply interface, because only one type of valve configuration must beproduced and installed in the liquid supply interface and operated. Inthis respect, what was said regarding the aforementioned valveconfigurations and as follows applies to the separating valveconfigurations accordingly.

In turn, in order to prevent undesirable bypass malfunctions, it ispreferably provided that the second connection flow path be the onlyliquid flow path extending between the second and the third couplingformation. This will ensure that the second and the third couplingformation can be separable from one another completely in afluid-mechanical manner through a single separating valve configuration.Likewise, the previously mentioned measure means that the first andsecond coupling formation are completely separable from one another in afluid-mechanical manner with the first separating valve configuration.To ensure reliable cleaning of the flow area, the connection formationconnected to a cleaning fluid reservoir and the connection formationconnected with a discharge or/and a disposal container are preferablyprovided such that, on the way from the first to the last, the first andthe second separating valve configuration must be in the outlet positionand thus in a position that the cleaning fluid flows through. This alsoensures cleaning of the two separating valve configurations when theflow area is flushed.

In order to achieve the previous functions: Introduction of cleaningfluid, introduction of fresh nutrient medium, removal of liquid samplesfrom a coupled cell culture container, and disposal of used nutrientmedium with the least-possible risk of subsequent cross-contaminationmay be provided according to a further advantageous embodiment of thepresent invention in that the second separating valve configuration isarranged such that the third liquid flow path can be separated from thesecond coupling flow path but not from the third coupling flow path bysaid configuration, and that the fourth liquid flow path can beseparated from the third coupling flow path but not from the secondcoupling flow path by said configuration, or that the fourth liquid flowpath can be separated from the second coupling flow path but not fromthe third coupling flow path by said configuration, and that the thirdliquid flow path can be separated from the third coupling flow path butnot from the second coupling flow path by said configuration.

The contactless signal- or/and power-transferring signaling means andcounter-signaling means may use, for example, an electric field betweeneach other for signaling or/and power transmission. To this end, thesignaling means and the counter-signaling means may each comprise anelectrode for establishing the electrical field between each other, inwhich the counter-signaling means may interact with a Piezo electricalactuator of the valve configuration such that the electric fieldestablished between the signaling means and the counter-signaling meansbrings about a structural change to the Piezo electrical actuator. Witha suitable installation of the Piezo electrical actuator into the valveconfiguration, the structural change of the Piezo electrical actuatormay, in turn, bring about an adjustment in the valve configurationbetween the blocked position and the outlet position. The material ofthe housing between the electrodes may act as a dielectric.

Due do the merely slight structural change of the Piezo electricalactuators, only slight flow gaps are expected to be established betweenthe valve bodies and the allocated valve seat with this configuration.However, these may be sufficient in order to adjust the valveconfiguration between the blocked position and outlet position, i.e. toestablish a state in which a liquid flow through the valve configurationis not possible (blocked position) and a state different from this inwhich such type of liquid flow is possible (outlet position).

Alternatively, the signaling means and the counter-signaling means mayhave a magnet and a ferromagnetic or/and magnetized component attractingits magnetic field. The effective magnetic field between the signalingmeans and the counter-signaling means may then cause shifting of thecounter-signaling means. The shifting of the counter-signaling meansmay, in turn, cause an adjustment of the valve configuration between theblocked position and the outlet position. This may be implemented, forexample, in the design in that the counter-signaling means is coupled toa valve body of a valve configuration for common movement, so that ashifting of the counter-signaling means lifts the valve body from itsvalve seat or places it back into contact at said seat. Thecounter-signaling means may also be in a particularly preferredembodiment of the valve body.

According to a further alternative, it may also be possible for thesignaling means to comprise a magnet and for the counter-signaling meansto comprise an electrically conducting component inductively attractingthe magnetic field of the magnet of the signaling means. In this case,the magnetic field effective between the signaling means and thecounter-signaling means can effect an induction in the counter-signalingmeans and this induction may, in turn, cause an adjustment in the valveconfiguration between the blocked position and the outlet position. Forexample, an actuator inductively placed in the housing, for example anelectric motor or an electric magnet with shiftable anchor, may besupplied with sufficient electrical power through induction in order todrive the actuator to move. A valve body coupled to the actuator canthus be raised from its valve seat and placed back in contact with saidseat.

Finally, in a technically more complex alternative, the signaling meansmay also comprise a transmitter of electromagnetic waves. These may beoptical signals or radio signals. The counter-signaling means thencomprises a corresponding receiver. The configuration may have a powerstorage unit surrounded by the housing and an actuator, which arecoupled to one another with the counter-signaling means such that thecounter-signaling means controls the actuator fed from the power storageunit for switching the valve configuration between the blocked positionand the outlet position, depending on the electromagnetic wavesreceived. In this case, signaling means and counter-signaling means areused like a remote control, somewhat comparable with the known remotecontrol of a television or a remote-controlled toy. The power storageunit surrounded by the housing of the liquid supply interface, whichaccording to definition should not be accessible from the exterior by aphysical signal- or power-transmitting connection, can be inductivelycharged as an electrical power storage unit. The actuator may, in turn,be an electric motor or an electric magnet with moving anchor, in which,in the latter case, the anchor can assume different positions dependingon the electrical state of the electric magnets. If the valve body of avalve configuration is coupled with a moving discharge part of theactuator for joint movement, the valve configuration can be switchedbetween the blocked setting and the outlet setting in a prudent manner.

For reasons of simple and robust design with simultaneously particularlysafe operation and ease of cleaning by the cleaning fluid that can flowthrough the signal area, that further embodiment of the aforementionedalternatives is preferred, according to which the signaling means andthe counter-signaling means comprise a magnet, on one hand, and aferromagnetic or/and magnetized component attracting its magnetic field,on the other hand, in which the counter-signaling means is preferably avalve body of the valve configuration for reasons of the least-possiblenumber of components, which can be shifted away from its valve seator/and toward said seat for sealing contact, under the effect of themagnetic field between the signaling means and the counter-signalingmeans.

In other words: the control configuration is formed for chronologicalor/and physical changing of a magnetic field starting from its at leastone signaling means according to a preferred further embodiment of thepresent invention.

Furthermore, this preferred embodiment enables the valve configurationto be pretensioned magnetically in the blocked position and adjustableinto the outlet position by the magnetic field starting from thesignaling means. This pretensioning can be implemented in the design inthat a valve seat of the valve configuration has a permanent magnet orferromagnetic tension component, such that a magnetic tension force,particularly attracting force, is in effect between the tensioncomponent and the valve body, which tensions the valve body for sealingcontact at the valve seat.

To ensure the most complete prevention of flow of the valveconfiguration and the blocked position, the valve seat may have anelastomer contact component, at which the valve body is directlypositioned in the blocked position of the valve configuration. By usingsuch an elastomer contact component, the valve body can penetrate intosaid contact component thus deforming the contact component due to themagnetic tensioning force and thus ensure flat contact of the valve bodyon the contact component. The elastomer contact component is preferablyan annular component with a through-flow opening, which is closed by thevalve body in the blocked position of the valve configuration andthrough which fluid can flow in the outlet position of the valveconfiguration. The magnetic tensioning force can be easily implementedin the design for deforming contact of the valve body at the elastomercontact component in that an attracting force is used as the magnetictensioning force between the valve body and the tension component, inwhich it is sufficient to allocate the elastomer contact componentbetween the valve body and the tension component. The elastomer contactcomponent can be formed from rubber, close-cell foam, silicone, and thelike. The tension component may consist of multiple sub-components,which however will make assembly more difficult. The tension componentis preferably a permanent magnetic annular component, which surrounds anopening, through which liquid can flow in the outlet position of thevalve configuration, as the preferred embodiment of the elastomercontact component.

For the aforementioned preferred case, in which the signaling means andthe counter-signaling means comprise a magnet, on one hand, and aferromagnetic or/and magnetized component attracting its magnetic field,on the other hand, the signaling means may comprise a locally shiftedpermanent magnet. By approximating the locally shiftable permanentmagnet at the counter-signaling means, which is preferably the valvebody itself, it can be removed from its pretensioning position, which ispreferably the blocked position of the valve configuration, which issynonymous with the activation of the valve configuration in the outletposition. The only requirement for this is that the magnetic fieldstarting from the permanent magnet of the signaling means acting on thevalve body (counter-signaling means) be stronger than the magnetic fieldstarting from the tension component, so that starting from a certainapproximation of the permanent magnet of the signaling means, themagnetic force starting from it and acting on counter-signaling means,which is preferably the attracting force, is greater than the magnetictensioning force starting from the tension component, so that themagnetic force starting from the permanent magnet prevails and causes anadjustment of the counter-signaling means, particularly of the valvebody.

In addition to or alternatively to a locally shiftable permanent magnet,the signaling means may comprise an electric magnet, which generates astrong magnetic field that is chronologically different depending on itsmagnetic current. With such type of electric magnet, a magnetic fieldcan also be generated through sufficiently strong magnetic currentsupply, the magnetic force of which overpowers the magnetic tensioningforce of the tension component and thus ensures an adjustment of thecounter-signaling means, particularly of the valve body. This will, inturn, cause switching of the valve configuration between the blockedposition and the outlet position

A particularly simple but effective control of the valve configurationof the liquid supply interface can then occur in that the controlconfiguration has a plurality of sets of signaling means, in which thesignaling means of a set each define a valve setting configuration ofvalve configurations of the liquid supply interface. Thus, a valvesetting configuration can be precisely defined using a set of signalingmeans. Depending on which set of signaling means the counter-signalingmeans will approximate in the liquid supply interface, different valvesetting configurations can thus be quickly and clearly activated withthe same low incidence of errors. The aforementioned operation forremoving liquid from a coupled cell culture container for cleaning andfor flushing the liquid supply interface and for introducing freshnutrient medium into a coupled cell culture container shows that, evenin the most complex structure of the liquid supply interface with threecoupling formations and four connection formations, essentially fixedvalve setting configurations suffice, namely one for a basic position(for example all valve configurations in the blocked position) during ashifting of the liquid supply interface between two coupling contactswith different cell culture containers for the removal of medium from acell culture container, for the cleaning of the liquid supply interfaceand/or its flow area, for the flushing of the same with fresh nutrientmedium, for the removal of a medium sample from the cell culturecontainer, and for the introducing of fresh nutrient medium into acoupled cell culture container. By providing six sets of signaling meansor one set of signaling means with six different switching states ifthere are electric magnets as the signaling means, the liquid supplyinterface can thus be fully operated.

A compact placement of these sets of signaling means can be attained inthe design in that the control configuration has a roller rotatingaround a roller axis, in which the plurality of signaling means sets arearranged distributed around the roller axis such that different valvesetting configurations of the liquid supply interface can be adjusted byrotating the roller.

The approximation of the signaling means sets, for example, by rotatingthe aforementioned roller, may suffice for clearly engaging theindividual valve configurations at a liquid supply interface. However,under some circumstances, there may be undesirable chronological offsetbetween the switching of different valve configurations of the liquidsupply interface.

The most precise possible switching of the valve configurations of theliquid supply interface can be achieved, in an advantageous manner, inthat the control configuration has a placement configuration, which isarranged between a signaling means and valve configuration adjustable bythe signaling means, in which the placement configuration has at leastone magnet that is shiftable between an active position closer to thevalve configuration and an inactive position closer to the signalingmeans, particularly permanent magnets.

For example, the placement configuration may have a shiftable magnet foreach signaling means of a set of signaling means.

The at least one shiftable magnet is preferably pretensioned in one ofits positions. To this end, it may have its own tensioning means. Saidtensioning means may be omitted, however, according to a preferredembodiment if the pretensioning of the at least one shiftable magnettakes place by utilizing the force of gravity. Preferably, the at leastone shiftable magnet is pretensioned in its inactive position so that itprevents an activation of the valve configuration allocated to it by thecontrol configuration without any further measures. According to aprevious preferred further embodiment of the present invention, thevalve configurations are pretensioned in their blocked position so thatflow-through of a valve configuration of the liquid supply interface isnot possible without additional measures. Thus, a failsafe measure isimplemented due to the further embodiment demonstrated here at theliquid supply interface.

Essentially it may also be possible to form the valve configurationssuch that they can be exclusively activated between the blocked settingand the outlet setting via the control configuration. However, it may beadvantageous in certain operating positions if they are permeable in anoutlet flow direction, regardless of their control configuration, due tosufficiently high liquid pressure in the allocated liquid flow path.Thus, filling of a cell culture container with fresh nutrient medium canbe supported, for example, regardless of the switching of a valveconfiguration. The introduction of cleaning fluid into the flow area canlikewise be supported.

According to an advantageous further embodiment of the presentinvention, it is thus intended for at least one part of the valveconfigurations, or preferably all valve configurations, to beadjustable, from the blocked position into the outlet position, in anoutlet flow direction along the liquid flow path, in which they arearranged, by means of a predetermined liquid pressure difference; thisdoes not apply to the opposite flow direction, in which preferably theoutlet flow direction of the first and of the second liquid flow path isdirected into the flow area and the outlet flow direction of the thirdliquid flow path is directed out of the flow area.

Advantageously, the cell culture containers at the counter-couplingformations are likewise equipped with valve configurations, as has beendescribed previously. The arrangement of a valve configuration at thecoupling flow paths can thereby be dispensed with when the couplingcontact is detached. This means the coupling formation of the liquidsupply interface preferably has no such type of valve configuration inorder to preferably reduce the components necessary for forming theliquid supply interface.

By providing valve configurations in the counter-coupling formations ofthe cell culture container, this also ensures that the filling of thecell culture container does not change after the coupling contactbetween the liquid supply interface in the cell culture container hasdetached, but instead the coupling flow paths remain blocked on the cellculture container side by a valve configurations provided for there.Preferably, the control configuration for common joint movement isconnected to the liquid supply interface. Thereby only the valveconfiguration and the counter-coupling formation of the respectivelyjust-coupled cell culture container can advantageously even be switchedoff due to sufficient approximation of the control and valveconfiguration.

The object mentioned at the beginning is attained according to anotheraspect of the present invention by a cell culture system with at leastone cell culture container for collecting and supplying adherent cellswith a nutrient medium reservoir, with a cleaning fluid reservoir, andwith a liquid supply point, as previously described and has beenadvantageously further demonstrated. The integration of the previouslydescribed liquid supply interface into the cell culture system with theremaining listed components takes place provided that:

-   -   the first connection formation connects the housing with the        nutrient medium reservoir in a liquid-transferring manner and        thus the first liquid flow path extends between the flow area        and the nutrient medium reservoir;    -   the second connection formation connects the housing with the        cleaning fluid reservoir in a liquid-transferring manner and        thus the second liquid flow path extends between the flow area        and the cleaning fluid reservoir;    -   the third connection formation connects the housing with a        discharge in a liquid-transferring manner and thus the third        liquid flow path extends between the flow area and the        discharge;    -   the coupling formation for coupling contact, which is producible        and detachable in a liquid-transferring manner according to the        operation, is formed with a counter-coupling formation of the        cell culture container;    -   the first liquid is the nutrient medium;    -   the second liquid is the cleaning fluid;    -   the coupling flow path is formed in order to remove nutrient        medium from the flow area and supply it to the cell culture        container or/and to remove it from said container and introduce        it to the flow area via the coupling formation, in a state        coupled with the counter-coupling formation.

This corresponds to the preferred connection pattern previouslydescribed in connection with operation of the liquid supply interface.Provided the previously mentioned advantages are indicated for theliquid supply interface, said advantages obviously also apply to thecell culture system, in which a liquid supply interface is accordinglyconnected at the nutrient medium reservoir, at the cleaning fluidreservoir, and at the closure. In the following description of the cellculture system, advantageous embodiments of the liquid supply interfaceand of the cell culture container that appear may obviously also beimplemented at the liquid supply interface and/or at the cell culturecontainer alone.

The cell culture container may further have the required number ofdelivery pumps order to convey the individual liquids into the fluidlines separately from one another.

The liquid-transferring coupling contact between the coupling formationof the liquid supply interface and the counter-coupling formation of thecell culture container may occur in a manner known from the prior art,for example through fluid-mechanical plug-socket connections, in which apin-type, i.e. male plug or connecting piece is inserted into a femalesocket, so that when the fluid-transferring coupling contact isestablished, a longitudinal section of a formation comprising thecoupling formation and the counter-coupling formation radially surroundsa longitudinal section of the respective other formation on theexterior. The coupling contact can be supported by a magnetic retainingmeans at the coupling formation and the counter-coupling formation. Inaddition or as an alternative to the magnetic retaining means,mechanical retaining means may also be provided, for example in the formof a destructible latch, which may be present between the couplingformation and the counter-coupling formation once theliquid-transferring coupling contact is established. The formationscomprising the coupling formation and the counter-coupling formationmay, however, exist without retaining means provided at the formationsthemselves, for example if a movement device, which moves the liquidsupply interface between the cell culture containers to be coupled,exerts a force onto said formations when coupling contact is establishedbetween the coupling formation and the counter-coupling formation, whichcounteracts detachment of the coupling contact.

The applicant moreover reserves the right to look for separateprotection for using a liquid supply interface, as has been previouslydescribed in its basic configuration and its preferred furtherembodiments, in a cell culture system for cultivating adherent cells.

As has been previously explained, the discharge at the longitudinal end,positioned away from the liquid supply interface, of the third liquidflow path may be a disposal drainage area or a disposal collectioncontainer, in which liquid is initially collected until a sufficientquantity is available in the disposal collection container and it isthen routed to a disposal location.

Essentially, the cleaning fluid may be liquid or gas. In order toachieve the maximum cleaning effect, the cleaning fluid is preferably acleaning liquid. The nutrient medium may essentially also be in liquidor gas form. Normally, the nutrient medium is present, however, as anutrient liquid in order to achieve maximum nutrient density.

As previously shown, the cell culture system may have a samplecollection device for grasping samples of the content of a cell culturecontainer, in which samples removed from the cell culture container arecollected until further processing thereof, for example through physicalor/and chemical analysis and testing. In order to avoid undesirablecontamination of the samples removed, the liquid supply interface mayhave the previously described forth connection formation. In this case,it is possible that

-   -   the fourth connection formation to connect a housing with a        sample collection device in a liquid-transferring manner on the        cell culture system, and thus the fourth liquid flow path        extends between the flow area and the sample collection device.

Because, in the cell culture system discussed in this case, cleaning ofthe flow area takes place by introducing the cleaning fluid into theflow area via the second connection formation and by removing thecleaning fluid from the flow area via the third connection formation,the most spatially extensive cleaning possible of the flow area canoccur by flushing it with cleaning fluid in that a flow path in the flowarea is the longest flow path between two valve configurations orbetween one valve configuration and one coupling formation, from thevalve configuration of the second connection formation to the valveconfiguration of the third connection formation. In this case, thecleaning fluid covers the longest flow path in the flow area betweenintroduction into the flow area and removal from said area, so that thecleaning fluid flows on said flow path flows through the largestpossible part of the flow area and wets and flushes wall sections ofsame.

In doing so, during the described flushing of the flow area withcleaning fluid, at least the line routes, of the flow area, leading toadditional connection formations can also be cleaned if, in the flowarea, a flow path passes by the valve configuration of the firstconnection formation and optionally by the valve configuration of thefourth connection formation, from the valve configuration of the secondconnection formation to the valve configuration of the third connectionformation.

The cleaning of the flow area of the liquid supply interface is thusbased on strategies that are characterized in the prior art as“Sterilize-In-Place” (SIP) or also “Clean-In-Place (CIP). To facilitatethe most effective SIP or CIP cleaning, which also cleans the valvebodies involved in the valve configurations in a flushing manner, it isadvantageous if the valves bodies of the valve configuration of thefirst connection formation and optionally the valve bodies of the valveconfiguration of the fourth connection formation at least partially, orpreferably at least more than halfway, penetrate into the flow path ofthe valve configuration of the second connection formation with respectto the valve configuration of the third connection formation. Thisfurther embodiment should expressly be understood as a furtherembodiment of the liquid supply interface on its own.

For the previously described reasons, it is advantageous if the cellculture container or containers have more than just one counter-couplingformation in order to achieve an increased hygiene standard, forexample, through separating the nutrient medium feed and the nutrientmedium discharge lines. According to an advantageous further embodimentof the cell culture system, it may be provided in concrete terms thatthe aforementioned counter-coupling formation of the cell culturecontainer be a first counter-coupling formation, that the cell culturecontainer have a second counter-coupling formation formed separatelyfrom the first counter-coupling formation, and that the cell culturesystem further have a liquid supply interface according to the previouspertinent description, provided that the first coupling formation isformed for coupling contact, which is producible and detachable in aliquid-transferring manner according to the operation, with the firstcounter-coupling formation, and that the second coupling formation isformed for a coupling contact, which is producible and detachable in aliquid-transferring manner according to the operation, with the secondcounter-coupling formation of the cell culture container, as well asthat the second coupling flow path extends between the flow area and thesecond coupling formation in order to remove nutrient medium from theflow area and supply it to the cell culture container or/and to removeit from said container and introduce it to the flow area via the secondcoupling formation, when there is coupling contact established with thesecond counter-coupling formation. The previous generally appliesaccordingly with respect to the counter-coupling formation and/or thecoupling formation to those formed from the first and the secondcounter-coupling formation and from the first and the second couplingformation.

Because, when a medium existing in the cell culture container isintended for proper hygienic sample removal, said medium may beimplemented at a further advantageously embodied cell culture system inthat the cell culture container has a third counter-coupling formationformed separately from the first and second, and that the cell culturesystem has a liquid supply interface according to the previous pertinentdescription, provided that the third coupling formation is formed forcoupling contact, which is producible and detachable in aliquid-transferring manner according to the operation, with the thirdcounter-coupling formation of the cell culture container, as well asthat the third coupling flow path extends between the flow area and thethird coupling formation in order to remove nutrient medium from theflow area and supply it to the cell culture container or/and to removeit from said container and introduce it to the flow area via the thirdcoupling formation, when there is coupling contact established with thethird counter-coupling formation.

In order to prevent media from escaping from the cell culture containerafter the liquid-transferring coupling contact has been detached betweenthe at least one coupling formation of the liquid supply interface andthe at least one counter-coupling formation of the cell culturecontainer, it is possible, with a further embodied cell culture system,for at least one counter-coupling formation, or preferably everycounter-coupling formation, of the cell culture container to have acontainer valve configuration.

Accordingly, the coupling formation may be free of a valve configurationat the liquid supply interface. The container valve configuration ispreferably set up as the extensively discussed valve configurations ofthe connection formations, to which description express reference ishereby made regarding discussion of the container valve configurations.

Consequently, it is preferable when the counter-coupling formation formsa male plug and the free coupling formation of the liquid supplyinterface forms a female socket for reducing the number of components,necessary for reducing their formation, preferably of a valveconfiguration.

Preferably, in order to achieve a high hygiene standard, the containervalve configuration is completely surrounded by the counter-couplingformation and the housing, with the exception of the liquid flow pathinterfusing the coupling formation and the counter-coupling formation,without a continuous signal- or/and power-transferring physicalconnection from the container valve configuration up to the exterior ofthe counter-coupling formation and of the housing of the liquid supplyinterface, when coupling contact is established between thecounter-coupling formation and the coupling formation.

If the coupling contact is not established, the container valveconfiguration may lie exposed at least partially at the counter-couplingformation. It may be covered by a cover, which can be removed from thecounter-coupling formation and be placed on said counter-couplingformation, between the times when there is coupling contact with acoupling formation. To this end, a suitable placement and removal devicemay be provided, which is either independently arranged in the cellculture system or formed to move jointly with the liquid supplyinterface. This removal and placement device may be formed, for example,by a multi-axis robot or by a moving gripper in a removal and placementdevice with the attachment at the liquid supply interface for commonmovement with said interface. This gripper may be driven, for example,by a spindle drive or a dual-acting piston-cylinder arrangement formoving in the removal and placement direction.

According to the preferred similar embodiment of the valveconfigurations of the connection formations and the at least onecontainer valve configuration, the latter may also be switchable betweena blocked position and an outlet position by the control configurationof the liquid supply interface. Thus, it is sufficient to provide onlyone common control configuration for the valve configurations of thecell culture container and for those of the liquid supply interface. Arequirement for this is that the container valve configuration bepretensioned in the blocked position and then only have to be switchedwhen a liquid-transferring coupling contact has been established betweenthe counter-coupling formation supporting the container valveconfiguration and a coupling formation of the liquid supply interface.Then the at least one container valve configuration and the valveconfigurations of the liquid supply interface may be spatially sotightly sealed with one another such that the switching can be easilyimplemented through a single common control configuration.

The possibility of being able to clean the at least one container valveconfiguration as well with cleaning fluid from the second to the thirdconnection formation when flushing the flow area can thereby be attainedin that a flow path, in the flow area, passes from the valveconfiguration of the second connection formation to the valveconfiguration of the third connection formation at the at least onecontainer valve configuration, or preferably at all container valveconfigurations, when coupling contact is established between the atleast one coupling formation of the liquid supply interface and the atleast one counter-coupling formation of a cell culture container. Inaddition, this will enable the cleaning of at least one part of thecoupling flow paths feeding into the flow path from the second to thethird connection formation.

A cleaning of particularly the container valve configurations byflushing the flow area can thereby be achieved in the design or evenimproved in that, when coupling contact is established between the atleast one coupling formation of the liquid supply interface and the atleast one counter-coupling formation of a cell culture container, thevalve body of the at least one container valve configuration, orpreferably said valve body of all container valve configurations,protrudes at least partially, or preferably at least more than halfway,into the flow path from the valve configuration of the second connectionformation to the valve configuration of the third connection formation.The container valve configurations with their valve bodies thuspreferably protrude precisely as far into the flow path from the valveconfiguration of the second connection formation to the valveconfiguration of the third connection formation as the valve bodies ofthe valve configurations of the connection formations. The advantagesmentioned in connection with the previous valve configurations,particularly with the cleaning thereof, also apply to the containervalve configurations.

To facilitate assembly, operation, and maintenance, the cell culturesystem can be further embodied such that all valve configurationsprovided in the liquid supply interface, or preferably also all valveconfigurations provided in the at least one cell culture container, areessentially constructed identically.

Advantageously for a cleaning of the flow area, the flow path extendsfrom the valve configuration of the second connection formation to thevalve configuration of the third connection formation in a straightline, or particularly preferably along an essentiallycircular-cylindrical channel in order to prevent intermeshing points.The relative movement direction of the valve bodies of the valveconfigurations of the second and of the third connection formation whenthey switch between the blocked position and the outlet positionpreferably extends along the flow path from the valve configuration ofthe second connection formation to that of the third connectionformation. The valve bodies of these valve configurations can thereby becovered by cleaning fluid on the largest possible area when the flowarea is flushed and thus be cleaned particularly well and reliably.

The previously mentioned elastomer contact component at which the valvebody of a valve configuration makes contact in its blocked position maynot only be used for sealing the passageway through the valveconfiguration but moreover can also be used for sealing off a connectionformation radially to the exterior. To this end, there may be a designprovision in at least one connection formation, or preferably in aplurality of connection formations, that an annular axial end face ofthe elastomer contact component, as a sealing surface that surrounds theliquid flow path allocated to the connection formation radially to theexterior, make contact, deformed, at a counter-sealing surface. Thecounter-sealing surface in this case may either be formed at the housingof the liquid supply interface or may be part of the fluid lineconnected in a liquid-transferring manner to the housing of the liquidsupply interface at the respective connection formation.

In a similar manner, the container valve configuration may also beprovided at a counter-coupling formation of a cell culture container andbe used to seal off the coupling contact established between thecounter-coupling formation and the allocated coupling-formation radiallyto the exterior with an annular axial end face. To this end, there maybe a provision that an annular axial end face of the elastomer contactcomponent of the container valve configuration make contact, deformed,at a counter-sealing surface of the liquid supply interface as thesealing surface surrounding the liquid flow path allocated to thecoupling formation radially to the exterior, when coupling contact isestablished between the at least one coupling formation of the liquidsupply interface and the at least one counter-coupling formation of acell culture container.

Preferably, the elastomer contact component may have a channelpassageway surrounded by an elastomer material, in which preferably theelastomer contact component has a conical recess, in which the valvebody is accommodated and at the negative-conical wall of which the valvebody has sealing contact in the blocked position of the valveconfiguration. The valve body in this case may be a cone itself orpreferably a sphere, due to the symmetry and the associated orientationinvariance.

If there is a conical recess provided at the elastomer contactcomponent, which widens down to an exposed longitudinal end pointingaway from the tension component, the annular axial end face remaining atthe longitudinal end of the conical recess may be particularly easilyused for sealing at the counter-sealing surface, as previously shown.

An essential advantage of the cell culture system according to theinvention is that it may have more cell culture containers than liquidsupply interfaces and media and liquid reservoirs such that a pluralityof separately formed cell culture containers can be supplied from oneand the same nutrient medium reservoir. In doing so, five liquid supplyinterfaces, for example, may be sufficient for the entire cell culturesystem. The risk of collision when moving the liquid supply interfacesbetween the individual cell culture containers can be further reduced byreducing the number thereof. Thus, it is preferable when the cellculture system has no more than three liquid supply interfaces. Inactuality, even one liquid supply interface may be sufficient in orderto supply a number of cell culture containers with fresh nutrient mediumand to remove used nutrient medium from the cell culture containers.

In order to move the at least one liquid supply interface between thecell culture containers to be coupled to it, the cell culture system mayhave a movement device. Said device is formed in order to bring the atleast one liquid supply interface into liquid-transferring couplingcontact with different cell culture containers one after the other. Apotential design of such a movement device may be a cross tableconfiguration with movement slides provided thereon, which provide amovement plane that is orthogonal with respect to the cross table plane,so that a liquid supply interface arranged on such type of movementdevice can be moved in at least three spatial directions that arelinearly independent. Alternatively, and this is preferred, the movementdevice may be a multi-axis robot, which offers a multitude oftranslational and rotational movement options depending on its number ofaxes. Other movement devices that enable the approaching of differentlocations in space are known to the average person skilled in the artfrom the prior art.

The object mentioned at the beginning is, moreover, attained as well bya cell culture container for an embodied cell culture system aspreviously described. Said cell culture container is formed forinteracting with the previously described liquid supply interface forestablishing and detaching a coupling contact with a coupling formationof the previously mentioned type.

Said cell culture container has a container body comprising a culturevolume with a fill opening through which gas, liquid, paste, or/andsolid bodies can be filled into the container body and removed from saidcontainer body. Thus, the aforementioned fill opening can be used inaddition or as an alternative or even as a ventilation opening.

According to the invention, such type of cell culture container isformed for establishing and detaching a coupling contact with a liquidsupply interface such that the cell culture container additionally hasat least one counter-coupling formation formed separately from the fillor/and ventilation opening, which is formed for establishing anddetaching a coupling contact with a corresponding coupling formation ofthe liquid supply interface, in which a delivery liquid flow pathextends between the at least one counter-coupling formation and theculture volume, in order to introduce a liquid into the culture volumeor/and to remove liquid from said culture volume via the delivery liquidflow path, in which the at least one counter-coupling formation has avalve configuration. The valve arrangement can preferably be switched bya control configuration with a signaling means generating an electricor/and magnetic or/and electromagnetic field, the field of which actsupon a correspondingly field-sensitive counter-signaling means of thevalve configuration without contact, between a blocked position, inwhich the valve configuration interrupts a liquid flow in the deliveryliquid flow path, and an outlet position, in which the valveconfiguration enables a liquid flow.

As has been previously shown, the container valve configuration in theat least one counter-coupling formation can maintain the seal closure insaid formation at any time at which there is no coupling contact betweenthe counter-coupling formation of the cell culture container and thecoupling formation of the liquid supply interface through pretensioningof the container valve configuration in the blocked position, such thatthe penetration of liquid through the counter-coupling formation intothe cell culture volume and the escaping of liquid from said volume canbe reliably prevented. The capacity to switch the container valveconfiguration enables the interruption of the delivery liquid flow pathto be established and rescinded in a targeted manner, for example if theaforementioned coupling contact has been established with the liquidsupply interface.

For further embodiment of the container valve configuration, expressreference is hereby made to the aforementioned statements regarding thevalve configuration preferred in this application, which is alsoapplicable to the container valve configuration.

In order to prevent collisions or to make it possible to have processingat the fill or/and ventilation opening itself if the at least onecounter-coupling formation is in coupling contact with the liquid supplyinterface, it may be advantageous for the fill or/and ventilationopening in the at least one separately formed counter-coupling formationto be provided at opposite ends of the cell culture container. This thusmakes it possible to access the culture volume of one and the same cellculture container at the fill or/and ventilation opening, on one hand,and at the at least one counter-coupling formation, on the other hand,at the same time without preventing access to the other one.

The significant advantage of the present invention is that particularlyadvantageous economical disposable cell culture containers can be used.Therefore, the cell culture container is preferably a passive container,which is implemented apart from the at least one container valveconfiguration of the at least one counter-coupling formation withoutfunctional units installed in the container, i.e. permanently connectedto the container, and driven by a power feed. Possible functional unitsuch as this are, for example, a heating mechanism or a stirringmechanism. Provided temperature control of the culture volume isnecessary for maintaining the cell cultures in the cell culturecontainer; this can be economically implemented in incubators or heatingcabinets into which the cell culture container can be placed, preferablytogether with other cell culture containers.

Preferably, the cell culture container is stackable, which is why it hastwo essentially parallel end walls and jacket wall sections surroundingan end wall edge, according to a preferred further embodiment of thepresent invention. End walls and jacket wall sections together delineatethe culture volume. It is further preferred when the end walls are thelargest-area wall sections of the cell culture container, in which thejacket wall sections may form a right angle with the end wallsadvantageously in order to increase stacking capacity.

To ensure that a plurality of cell culture containers may be stacked ina stable manner by placing the preferably largest end walls of thedirectly adjacent cell culture containers next to one another,preferably the at least one counter-coupling formation, or especiallypreferably also the fill or/and ventilation opening, is provided in ajacket wall section. Thus, the end walls may be free of functionalelements and provide maximum size and a stable stacking surface.

The further embodiments addressed in connection with the liquid supplyinterface or/and with the cell culture system for cell culturecontainers, for example the provision of two or even threecounter-coupling formations, of which preferably each is provided with acontainer valve configuration, also apply to the cell culture containeras an application subject matter by itself.

Preferably, the at least one counter-coupling formation is formed as amale coupling connecting piece, which is formed by a coupling socket ofthe coupling formation of the liquid supply interface radially to theexterior in the coupling contact.

The culture volume (total volume) of the cell culture container ispreferably no greater than 2 L, or especially preferably no greater than1.3 L. Thus, in the event of individual contaminated cell cultures, thetotal damage can be significantly limited.

The present invention is explained in more detail in the following usingthe accompanying drawings. The following is shown:

FIG. 1 shows a longitudinal sectional view through an embodimentaccording to the invention of a cell culture container, on which twocounter-coupling formations are provided as an example.

FIG. 2 shows a sectional view through an exemplary embodiment accordingto the invention of a liquid supply interface, which is inliquid-transferring contact with the cell culture container from FIG. 1.

FIG. 3 shows a longitudinal sectional view of the liquid supplyinterface and of the cell culture container in section plane III-III ofFIG. 2 with a control configuration, which has a placement configurationprovided between signaling means and the liquid supply interface.

FIG. 4 shows a detailed view of a coupling formation of the liquidsupply interface from FIG. 2 and a counter-coupling formation of thecell culture container of FIGS. 1 to 3 in a state in which no couplingcontact has been established between them.

FIG. 5 shows the components from FIG. 4 with liquid-transferringcoupling contact established between them.

FIGS. 6-14 show representations of different valve switching states(valve position configurations) of a cell culture system according tothe invention with a liquid supply interface with a first to fourthconnection formation and with a cell culture container according toFIGS. 1 to 3.

FIGS. 15-18 show different valve switching states (valve positionconfigurations) of a second embodiment of a cell culture systemaccording to the invention, in which cell culture containers are beingused with three counter-coupling formations each.

FIGS. 19-21 show representations of different valve switching states(valve position configurations) of a third embodiment of a cell culturesystem according to the invention, which uses cell culture containerswith only one single counter-coupling formation each.

FIG. 1 shows an exemplary embodiment according to the invention of acell culture container generally characterized as 10. Such type of cellculture container may be used in a cell culture system according to theinvention.

The cell culture container 10 has a container body 12, which encloses aculture volume 14.

The container body 12 of the cell culture container 10 preferably hastwo essentially parallel end walls; FIG. 1 only shows the end wall 16 tothe rear of the cutting plane due to the cutting plane of this figureparallel to the end walls. Jacket wall sections, which are cut by thecutting plane in FIG. 1, are provided between the two end walls 16.

Of the jacket wall sections, the two lateral jacket wall sections, 18and 20, are preferably parallel with respect to one another, and thefront and rear jacket wall sections, 22 and 24, are parallel withrespect one another. To facilitate stacking of cell culture containers10 according to the invention, the aforementioned jacket wall sections,20, 22, 24, preferably are adjacent and among them form a right angle.It is further preferable that each of the jacket wall sections, 18 to24, form a right angle with the parallel end walls.

However, this does not rule out the possibility that the jacket wallsections also have jacket wall sections, 26 and 28, that preferably forma right angle with the end walls but not with their adjacent jacket wallsections 18 and 22 or 20 and 22. For example, these jacket wallsections, 26 and 28, may extend tilted toward the front jacket wallsection 22 such that the container body 10 tapers toward the front wallsection 22.

The container body 10 has an access opening 30, which may be used as afill or/and ventilation opening for filling or emptying the culturevolume 14 or for the ventilation thereof. Preferably, the access opening30 is formed at an access neck 32, which can be optionally closed oropened by a closure cover 34. The closure cover 34 may be formed as athreaded cap with an internal thread for better retention at the accessneck 32, with the internal thread having an outer thread preferablyprovided at the exterior of the access neck 32, which can be screwed onin a known manner. If there is ventilation of the culture volume 14,i.e. an exchange of gas between the culture volume 14 and the outerenvironment of the cell culture container 10, even when an otherwiseclosed access opening 30 is desired, the closure cover 34 may have oneor more breach openings in its front case 36 oriented orthogonally withrespect to the drawing plane in FIG. 1 in the example, through which gasmay be able to pass into the culture volume 14 and flow back out of it,but the dimensions of which are selected such that typical laboratorydevices cannot pass through them.

Preferably, the cell culture container 10 is an economical disposablecell culture container without the electrically driven heating mechanismformed thereon and without the electrically driven stirring mechanismprovided thereon. For better monitoring and observing of the cellculture process, the container body 12 is preferably formed at least insections, or preferably completely, of optically transparent plastic,for example made of polymethyl methacrylate (PMMA) or another suitabletransparent plastic, depending on the desired chemical resistance, as afunction of the expected chemical or biochemical materials, that are onthe inside of the culture volume 14 according to the operation.

The cell culture container 10 further has one or more counter-couplingformations 38, in precisely two counter-coupling formations, 38 and 40,in the example shown in FIG. 1.

The cell culture container 10 may have any number of counter-couplingformations considered by themselves, in which even the number of threecounter-coupling formations provides separate delivery liquid flow pathsfor filling, emptying, and for random sampling of the culture volume 14or from the culture volume 14. If a third counter-culture formation isdesired in the embodiment of a cell culture container 10 shown in FIG.1, this can be arranged in the center between counter-couplingformations 38 and 40 that are indicated, as shown by the dash/dottedline of the delivery liquid flow path of said third counter-couplingformation.

In the event only one single counter-coupling formation is desired, itcan be provided at any of the three places shown in FIG. 1, or even atany of the other places in a different jacket wall section or even in anend wall.

The stacking capacity of the cell culture containers 10 by placing themone on top of the other at their end walls is, however, facilitated inan advantageous manner in that both the access opening 30 as well as allof the counter-coupling formations, 38 and 40, are provided at jacketwall sections. The accessibility of the counter-coupling formations, 38and 40, on one hand, as well as the access opening 30, on the otherhand, independently of one another can be improved even more in that, asshown in FIG. 1, counter-coupling formations 38 and 40 and the accessopening 30 are formed at different jacket wall sections, 22 and 24,which are preferably opposite one another. In this case, even accessopenings 30 can be accessed by an operator at cell culture containers 10stacked on top of one another and next to one another on one side of thestack wall, and the counter-coupling formations, 38 and 40, can beaccessible through a liquid supply interface, described in more detailbelow, on the opposite side of the stack wall.

The counter-coupling formations, 38 and 40, are formed preferablyidentically to facilitate production and assembly, which means that onlyone counter-coupling formation is described representatively for allcounter-coupling formations provided on the cell culture container 10 inthe following.

The counter-coupling formation 38 has a counter-coupling formationhousing 42, which may be formed as a single piece, or in multiple piecesas shown in FIG. 1. The housing 42 defines a first delivery liquid flowpath 44, which extends between the outer environment of the cell culturecontainer 10 and its culture volume through the first counter-couplingformation 38.

The counter-coupling formation housing 42 may have a housing accesscomponent 45 further away from the cell culture container 10, which maybe permanently connected to the housing support component 46, which iscloser to the cell culture container 10. This connection may, forexample, be a threaded connection, particularly in that the housingaccess component 45 is screwed onto a threaded shaft of the housingsupport component 46.

Preferably, the housing support component 46 is used for fastening thefirst counter-coupling formation 38 onto the cell culture container 10,for example in that a fastening shaft 48 of the housing supportcomponent 46 penetrates an allocated opening 50 in a wall of the cellculture container 10. The fastening shaft 48 may be affixed with theknown fastening means in the particular wall of the cell culturecontainer 10, for example by means of mechanical fastening and sealingmeans 1, which are not shown in more detail in FIG. 1, but which,however, are commonly known to the average person skilled in the art,inserted into a circumferential groove 52. In addition or as analternative to this, the counter-coupling formation housing 42 may bebonded or/and welded to the container body 12.

Preferably, the counter-coupling formations, 38 and 40, are provided ata jacket wall section, particularly at a jacket section 22 having theaccess opening 30, which is diametrically opposed to jacket wall section24.

The first counter-coupling formation 30 may further have a containervalve configuration 54, which can be switched between a blocked positionand an outlet position. The container valve configuration 54 of thefirst counter-coupling formation 38 is shown in its blocked position inFIG. 1, in which it interrupts the delivery liquid flow path 44. In itsoutlet position, which is not shown in FIG. 1, the container valveconfiguration 54 enables a liquid flow along the delivery liquid flowpath.

Even though the container valve configuration 54 may be completelysurrounded by the housing 42 of the first counter-coupling formation,with the exception of the delivery liquid flow path 44, it is preferablyprovided at the access-side longitudinal end area of the firstcounter-coupling formation 38. This facilitates its cleaning when theliquid supply interface is coupled, which is described in the following.

The container valve configuration 54 has a valve body 56, which ispositioned on a valve seat 58 with a negative-conical contact surface,in the blocked position shown in FIG. 1. For reasons of improved sealingcapacity, the valve seat 58 preferably has a contact component made of amaterial, which deforms slightly under the pretensioning force acting inthe blocked position in the container valve configuration 54. Suitablematerial includes, for example, an elastomer plastic material such assilicone, rubber, or a liquid-impermeable, closed-cell plastic, such asPU foam, or the like.

The valve body 56 is preferably formed as a sphere for reasons ofsymmetry, so that, for its function, it does not reach its orientationrelative to the valve seat 58.

The valve seat preferably has a tension component 60, which in thepresent case is formed as a permanent magnet, on the side of the contactcomponent 59 facing away from the valve body 56. The permanent magnetictension component 60 is preferably formed in the shape of a ring and ispenetrated by the allocated delivery liquid flow path 44, just as thecontact component 59.

As described in more detail below in connection with FIGS. 4 and 5, thecontact component 59 not only serves as a sealing contact of the valvebody 56, but also is a sealing contact at a counter-sealing surface ofthe liquid supply interface, which is formed to establish aliquid-transferring coupling contact with the counter-couplingformations, 38 and 40, provided at the cell culture container 10.

FIG. 2 shows the longitudinal end of the cell culture container 10 shownin FIG. 1 on the counter-coupling formation side, which is inliquid-transferring coupling contact with a liquid supply interface 62via its counter-coupling formations, 38 to 40.

In the example shown in FIG. 2, the liquid supply interface 62 has afirst coupling formation 64, which is in coupling contact with the firstcounter-coupling formation 38 and has a second coupling formation 66,which is in liquid-transferring coupling contact with the secondcounter-coupling formation 40. The first and the second couplingformation, 64 and/or 66, are preferably formed as sockets in the housing68 of the liquid supply interface 62.

When only one container valve configuration 54 is provided on thecell-culture-container side at the coupling point of the couplingformation and the counter-coupling formation, the housing 68 of theliquid supply interface 62 has exactly the same number of couplingformations as the cell culture container 10 to be coupled hascounter-coupling formations. Accordingly, the liquid supply interface 62may have only one or even three or more coupling formations.

The housing 68 of the liquid supply interface 62 is advantageouslyconstructed in multiple pieces. However, this is not mandatory. If thehousing comprises multiple pieces, it is preferable if separatingsurfaces are placed between the individual housing parts orthogonallywith respect to a liquid flow path formed at the respective housing partand are penetrated by the liquid flow path. The individual housing partsare attached to one another using screws 70 in the example shown. As analternative or in addition to the threaded connection, individual or allhousing parts connected to one another may be welded or/and bonded toone another.

The housing 68 initially defines a flow area 72, which is divided intotwo sub-flow areas, 72 a and 72 b, by a separating valve configuration74, with the two sub-flow areas situated on both sides of the separatingvalve configuration 74. A connecting flow path 75 proceeding between thetwo coupling formations, 64 and 66, extends through the separating valveconfiguration 74 in the example shown.

Advantageously, both sub-flow areas, 72 a and 72 b, are formedcircular-cylindrically except for the start, end, and intermediatefeeds, which significantly facilitates cleaning in the CIP process or inthe SIP process as explained below.

The coupling formations, 64 and 66, are shown as formed with differentdiameters in the example shown in FIG. 2 in order to indicate that, evenwith coupling contact established between the coupling formation and thecounter-coupling formation, it is advantageous when a section of aformation comprising the coupling formation and the counter-couplingformation surrounds an axial section of the respective other formationradially on the exterior, but the two formations do not necessarily haveto make contact with one another in the area of this encompassingsection. The larger clear width of the second coupling formation 66 ascompared to the outer diameter of the second counter-coupling formation40 facilitates the establishment of the coupling contact between thecoupling formation 66 and the counter-coupling 40 significantly withoutfearing that the seal will be compromised. It is important in this casethat the liquid supply interface 62 be routed at a correspondingmovement device sufficiently precisely in order to establish couplingcontact.

The embodiment of the liquid supply interface 62 shown as an example inFIG. 2 has a first connection formation 76, a second connectionformation 78, and a third connection formation 80. The first connectionof formation 76 defines a first liquid flow path 82, which extendsbetween the flow area 72, which is more precisely the sub-flow area 72 ain the present example, and the first connection formation 76, andfurthermore into the first connection formation 76.

At its longitudinal end 76 a positioned away from the flow area 72, theconnection formation 76 is formed, for example, by an adapter piece 76 a1, in order to connect with a fluid line 84, which, in the example shownin FIG. 2, preferably leads to a nutrient medium reservoir, which is notshown in FIG. 2 (see FIG. 6 ff.). The fluid line 84 is preferably aflexible fluid line, for example made of an elastomer hose, which isplaced onto the adapter piece 76 a 1 and there can be secured againstundesirable removal with securing means in a known manner, for example ahose clamp.

Nutrient medium can be introduced into the flow area 72 and thendistributed out from there through the fluid line 84, i.e. along thefirst liquid flow path 82. For example, fresh nutrient medium can beintroduced into the culture volume 14 of the cell culture container 10along the delivery flow path 44, via the first coupling formation 64 andthe first counter-coupling formation 38.

The fluid line 84 may also be formed as a rigid pipeline, but this isless preferred, because the nutrient medium reservoir must also be movedalong with the liquid supply interface 62.

In the coupled state shown in FIG. 2, that particular part of thedelivery liquid flow path 44 that extends into the flow area 72 in thearea of the first coupling formation 64 is identical to a coupling flowpath 44 a that extends between the flow area 72 in the first couplingformation 64. When liquid-transferring coupling contact is establishedbetween the first counter-coupling formation 38 and the couplingformation 64, the first coupling flow path 44 a merges from the flowarea 72 into the delivery flow path 44. These flow paths are thencollinear. The same thing applies to the second delivery liquid flowpath 47 of the second counter-coupling formation 40 and the secondcounter-coupling path 47 a of the second coupling formation 66.

The first connection formation 76 may be formed in multiple pieces, asis shown in FIG. 2. A multi-piece formation supports in this case theassembly and subsequent maintenance of the liquid supply interface 62.

The first connection formation 76 has a valve configuration 86 at thelongitudinal end 76 b, of the first connection formation 76, closer tothe flow area 72. The valve configuration 86 is constructed identicallyto the container valve configuration 54 of the first and the secondcounter-coupling formation, 38 and/or 40, which means that similar andfunctionally similar components and component sections have been giventhe same reference characters as those for container valve configuration54 at valve configuration 86. Otherwise, in order to describe valveconfiguration 86, express reference is made to the description of thecontainer valve configuration 54 indicated in the present application,which also applies not only to the first connection formation 76 butalso the other connection formations, 78 and 80, for valve configuration86.

Due to the preferred permanent fastening shown in FIG. 2 of theconnection formation 76 at the housing part, directly defining the flowarea 72, of the liquid supply interface 62 by means of the screws70—which moreover do not penetrate into the flow area 72 contrary towhat is shown in FIG. 2, but rather lie in front of the drawing plane inFIG. 2 as can be seen in FIG. 3—the valve arrangement 86 of the firstconnection formation 76 is completely surrounded by the housing 68 withthe exception of the first liquid flow path 82. The valve body 56 ispreferably a sphere made of ferromagnetic material, which ispretensioned in its blocked setting against the elastically deformablecontact component 59 of the valve seat 58, by the permanent-magnetictension component 60.

The second and the third connection formation, 78 and/or 80, are eachformed identically to the first connection formation 76, such thatreference is expressly made to the description of the first connectionformation for the description thereof.

Preferably, an adapter piece 78 a 1 provided at the longitudinal end 78a away from the flow area is connected to a second fluid line 88, whichis connected to a cleaning fluid reservoir, which is not shown in FIG.2, on the other end. A second liquid flow path 90 further extendingbetween the flow area 72, shown more precisely as sub-flow area 72 a inFIG. 2, and the second connection formation 78 enables, in the exemplaryembodiment shown in FIG. 2, i.e. preferably an introducing of cleaningfluid from the cleaning fluid reservoir, not shown, into the flow area72, which is more precisely into sub-flow area 72 a. Thus, a maximumlength of the flow area 72 is accessible by the cleaning fluid, andpreferably the second connection formation 78 is provided at an axiallongitudinal end of the flow area 72.

The third connection formation 80 is preferably connected to adischarge, which is not shown in FIG. 2. This can be done through afluid line (not shown in FIG. 2) mounted onto the third connectionformation 80 in the manner previously described with reference to thefirst and the second connection formation, 76 and 78, respectively.

A third liquid flow path 92, through which liquid in the liquid flowarea 72 can be removed from said area and routed to a discharge,furthermore extends between the liquid flow area 72, more preciselybetween sub-flow area 72 b as indicated in FIG. 2, and the thirdconnection formation 80.

In order to route cleaning fluid introduced into the flow area 72through the second liquid flow path 90 via the longest section of theliquid flow area of 72 possible and thus in order to clean the largestsection of the liquid flow area 72 possible, it is preferable for thethird connection formation 80 to be arranged at the longitudinal end ofthe flow area 72 opposite the assembly point of the second connectionformation 78. Thus, cleaning fluid introduced through the secondconnection formation 78 into the flow area 72 cannot be removed fromsaid area via the third connection formation 80 until it has passedthrough essentially the entire flow area 72. Thus, the flow area 72 canessentially be flushed with cleaning fluid over its entire length viathe second and third connection formation, 78 and 80, respectively.

To ensure that the entire liquid supply interface 62 including thecounter-coupling formations, 38 and 40, currently in coupling contactwith said interface can be cleaned as efficiently as possible with suchtype of cleaning process before the culture volume 14 of therespectively coupled cell culture container 10 has fresh nutrient mediumrouted to it or existing nutrient medium is drained from it, all feedpoints of a further connection formation or of a coupling formation inthe flow area 72 are preferably located between the second connectionformation 78 and the third connection formation 80, so that they arepositioned along the aforementioned flushing path and can be reached bycleaning fluid flowing from the second connection formation 78 to thethird connection formation 80.

In order to clean the valve bodies 56 of the valve configurations 86 andthe container valve configurations 54 as well as the separating valveconfiguration 74 as efficiently as possible, they penetrate either intothe flow area 72 or are located completely within it. The valve bodies56 preferably penetrate into the flow area 72 with at least more thanhalf of their body volume.

FIG. 3 shows the arrangement shown in FIG. 2, characterized by arrowIII-III, in the orthogonal cutting plane with respect to the drawingplane from FIG. 2. In this case, FIG. 3 shows a control configuration94, which is preferably arranged under the assembly comprising theliquid supply interface 62 and the cell culture container 10 coupledthereto. The position of the second valve configuration 86 in the secondconnection formation 78 and the valve position of the separating valveconfiguration 74 differ in FIG. 3 from those in FIG. 24 purposes ofexplanation.

The control configuration 94 may have a roller 96 rotating around aroller axis W, which may be driven by a drive 98, for example anelectric motor drive for rotating around the roller axis W.

A plurality of signaling means 100 may be arranged around the peripheryof the jacket surface 96 a of the roller 96, which are formed bypermanent magnets in the present example. These permanent magnets arepreferably oriented such that their N-S polarization directioncorresponds to a radial direction starting from the roller axis W.

In doing so, the liquid supply interface 62 in coupling contact with acell culture container 10, that is part of the signaling means 100, iscombined into a set 102 of signaling means for a concrete valvepositioning configuration of the valve configurations 54, 74, and 86.Thus, the row of six signaling means 100 placed above the roller axis Wpositioned in the cutting plane in FIG. 3 forms such type of set.

Diametrically opposed to this is another set of signaling means, which,however, is not indicated in FIG. 3. Instead of this, only thecollection areas provided for the signaling means are shown in theroller 96. Between said areas, additional sets of signaling means may beprovided along the periphery of the roller 96.

The placement configuration 104 may be provided between the liquid valveinterface 62 and the cell culture container in coupling contact with it,on one hand, and the roller 96, on the other hand, in order to enableeven more chronologically precise switching of the valve configurations54, 74, and 86.

As in a set 102 of signaling means 100 of the roller 96, it is alsopreferable in the placement configuration for every switchable valveconfiguration 54, 74, 86 of a valve position configuration to haveprecisely one permanent magnet 106. Each permanent magnet 106 in thiscase is placed so as to shift, in a channel 108, along said channel 108,so as to shift between a position closer to the roller and a positioncloser to the valve configuration.

The permanent magnets 106 in this case are selected such that themagnetic field starting from them and acting upon the valve body 56 isstronger, at least in the position closer to the valve configuration,than the magnetic field starting from the magnetic tension components 60and acting upon the respective valve body 56. In addition, the magnets106 are preferably arranged polarized along their shifting axis,designed such that one pole, for example the north pole, references therespectively allocated valve configuration, and the respective otherpole, for example the south pole, references the roller 96.

The placement configuration 104 is preferably arranged such that thepermanent magnets 106 are pretensioned in their position closer to theroller in the respective channels 108 by the force of gravity indicatedby the arrow g, in which, for example, permanent magnet nos. 2, 3, 5, 6(when counting from left to right) are located in FIG. 3.

With the corresponding placement of the signaling means 100, thepermanent magnets 106 are shifted from their position closer to theroller to their position closer to the valve configuration, for exampleby placing like poles opposite one another, i.e. repellent poles ofpermanent magnets 106 and signaling means 100, with the approximation ofsaid signaling means 100 to the permanent magnets 106 of the placementconfiguration 104 by the magnetic fields starting from the signalingmeans 100. By placing like poles, i.e. poles that attract one another,of permanent magnets 106 and signaling means 100 opposite one another,the permanent magnets 106 are magnetically held in the position closerto the roller, in addition to the constantly acting force of gravity.

Upon approximation of a magnet 106 of the placement configuration 104 atthe valve configuration allocated to it, the valve body 56 of same ismore strongly pulled by the permanent magnet 106 located in its positioncloser to the valve configuration than by the tension component 60 ofthe respective valve configuration. The valve body 56 thus moves fromits blocked position, in which it has contact with the contact component59 to form a seal of a passageway opening through the valveconfiguration, in a position in which a passageway is possible throughthe respective valve configuration, and thus a flow is enabled along thevalve flow path allocated to the valve configuration.

With the example shown in FIG. 3, the valve body 56 of the valveconfiguration 86 of the second connection formation is removed from itsvalve seat 58, particularly from the contact component 59, by thecontrol configuration 94, such that the second liquid flow path 90 isexposed to the flow of a liquid, which in this case is cleaning fluid.

The separating valve configuration 74 is likewise adjusted in its outletposition by the control mechanism 94 in the position shown in FIG. 3,because its valve body 56 is also shifted away from the contactcomponent 59 toward the allocated fourth permanent magnet of theplacement configuration 104. Thus, in addition to the second liquid flowpath, the connection flow path 75 extending between the first couplingflow path 44 a and the second coupling flow path 47 a is also exposedfor the flow of liquid.

In the present example, there is a 1:1 allocation between the signalingmeans 100 and the valve configurations, 54, 74, and 86, which areavailable at a liquid supply interface 62 coupled to a cell culturecontainer 10. There is also such type of 1:1 allocation between themagnets 106 of the placement configuration 104 and the existing valveconfigurations. The signaling means 100 and the permanent magnets 106arranged all the way to the left in FIG. 3 are allocated to the secondvalve configuration 86 in the second connection formation 78. Theirneighbors to the right, as signaling means 100 or permanent magnet 106,are allocated to the first container valve arrangement 54 at the firstcounter-coupling formation 38. Their respective neighbors to the rightin FIG. 3 are allocated to the first valve configuration 86 of the firstconnection formation 76. Their neighbors to the right are allocated tothe separating valve configuration 74. Their neighbors to the right areallocated to the second container valve configuration 54 of the secondcounter-coupling formation 40, and the combination comprising signalingmeans 100 and permanent magnet 106 all the way to the right in FIG. 3 isallocated to the third valve configuration 86 of the third connectionformation 80.

The sets 102 of signaling means 100 distributed around the periphery ofthe jacket surface 96 a of the roller 96 have signaling means 100, eachof which are arranged differently in their polarization, in order toadjust the valve position configuration, allocated to the respectivesignaling means set 102, of all six involved valve configurations, 54,74, and 86, by approximation of the respective set 102 of signalingmeans 100 to the placement configuration 104.

The position of valve configurations 54, 74, and 86 shown in FIG. 3 isonly exemplary in nature and not assigned any concrete function.

FIGS. 4 and 5 show an example of how the contact component 59 of thevalve configurations 54 shown in the present embodiment are used to sealthe coupling point between the first coupling formation 64 on the supplyinterface side and the counter-coupling formation 38 on the cell culturecontainer side. The principal demonstrated here also applies, however,to the coupling comprising the second coupling formation 66 and secondcounter-coupling formation 40 and would also apply at the coupling pointof a potential third coupling formation and third counter-couplingformation.

In a similar manner, the separating surfaces extending in a longitudinalend away from the tension component advantageously constrained by theassembly between individual components of the housing 68 of the liquidsupply interface 62 according to the principle shown in FIGS. 4 and 5 issealed off by the deforming contact of the contact component 59 at acounter-sealing surface of another housing component.

FIG. 4 shows the first counter-coupling formation 38 not in contact withthe allocated first coupling formation 66, which means that while thevalve body 56 forms a sealing contact at the negative-conical contactsurface 59 a of the contact component 59—based on the magnetictensioning force starting from the tension component 60—the contentcomponent 59 is otherwise essentially not deformed. The contactcomponent 59 has a surrounding face ring surface 59 b at itslongitudinal end away from the tension component. In the example shown,this ring surface 59 b is oriented orthogonally with respect to thedrawing plane in FIG. 4. In this state, the counter-coupling formationcan be covered by a push-on cover 61, shown on one side and indicated bythe dashed line, and protected from contamination.

The coupling formation 36 has a counter-sealing surface 64 a, which isformed, when a liquid-transferring coupling contact is establishedbetween the first coupling formation 64 and the first counter-couplingformation 38, to attain contact with the annular-shaped end face (facering surface) 59 b of the contact component 59.

FIG. 5 shows the first coupling formation 64 and the firstcounter-coupling formation of 38 when the coupling contact isestablished, as can also be seen in FIG. 2.

There it can be seen how the longitudinal end, further away from thetension component, of the contact component 59 with its face ringsurface 59 b is attained, with deformation, in contact with the countersealing surface 64 a of the housing component, having the first couplingformation 64, of the housing 68 of the liquid supply interface 62. Thecoupling point and particularly the coupling flow path 44 a and thedelivery liquid flow path 44 are sealed off radially to the outsideagainst undesirable escaping of liquid through this deforming contact.The same thing applies to any undesirable inlet of liquid into theseliquid flow paths.

This previous description in FIGS. 4 and 5 applies to the radial seal ofall valve configurations shown in the embodiment discussed here.

FIGS. 6 to 14 show by means of diagrams an example operating process ofa cell culture system with cell culture containers 10 according to FIG.1 and with a modified liquid supply interface 62′, which has a fourthconnection formation, contrary to the liquid supply interface 62 shownin FIGS. 2 and 3. The fourth connection formation is identified as 110in FIGS. 6 to 14 (as well as FIGS. 15 to 21). It also has a valveconfiguration 86. The fourth liquid flow path, which proceeds from theflow area 72 through the fourth valve configuration 86 of the fourthconnection formation 10 and beyond, has the reference character 112.

The cleaning fluid reservoir is identified as 114. The nutrient mediumreservoir has the reference character 116. A disposal containerconnected to the third connection formation 80 is identified as 118. Thesampling container 120, in which samples removed from the respectivelyconnected cell culture container 110 are collected, is connected to thefourth connection formation 110.

Delivery pumps 122, which are of no further interest and which ensurethe delivery of liquids into the fluid lines connected to them in therespectively desired conveying direction, are provided between therespective first to fourth connection formations 76, 78, 80, and 110 andthe reservoirs or containers 114, 116, 118, and 120 connected to themvia fluid lines.

FIG. 6 shows a basic valve position configuration, as is present when aliquid-transferring coupling contact is established between the firstand the second coupling formation, 64 and 66, and the first and thesecond counter-coupling formation, 38 and 40, respectively. All existingvalve configurations, 54, 74 and 86 in this case are in their blockedposition in order to prevent any undesirable flow of liquid.

FIG. 7 shows an SIP process, which is preferably after the establishmentof the coupling contact, with which a predetermined cleaning conditionis established at the container valve configurations 54 and in theliquid supply interface 62′. To this end, the separating valveconfiguration 74 and the valve configurations 86 of the second and ofthe third connection formation, 78 and 80 respectively, are switched totheir outlet position. By means of the pump 112 coupled to the cleaningfluid reservoir 114, cleaning fluid is removed from the reservoir 114and routed through the second connection formation 78 into the flow area72; it continues further through this area and is pumped through thethird connection formation 80, optionally with the support of thedelivery pump 122 connected to the liquid flow path 92 in the disposalcontainer 118. Due to the penetration of the valve body 56 into the flowarea 72 flushed with cleaning fluid, the valve configurations 54, 74,and 86 involved are also cleaned, which establishes a cleanlinesscondition, which prevents cross-contamination between cell culturecontainers 10 that are coupled at different times.

FIG. 8 shows random sampling following the previously discussed SIPcleaning process. The selection of the sequence of media removal from acell culture container 10 before said media are introduced has theadvantage that an introduction of nutrient medium into the cell culturecontainer 10 does not take place until after an additional cleaningprocess, which further reduces the risk of cross-contamination due tocontamination of a cell culture container 10 previously in couplingcontact.

For random sample medium removal, the container valve configuration 38of the first counter-coupling formation is switched to its outletposition. In addition, the valve configuration 86 of the fourthconnection formation 110 is switched to its outlet position. All othervalve configurations are in their blocked position. Thus, with thedelivery pump 122 provided between the fourth connection formation 110and the sampling container 120, a predetermined quantity of medium canbe removed from the culture volume 14 of the coupled cell culturecontainer 10 and placed into the sampling container 120. The separatingvalve configuration 74 in this case ensures that the sub-flow area 72 ais not reached by the medium removed from the cell culture container 10.

FIG. 9 shows a discharge, which is advantageously following thesampling, of used nutrient medium from the culture volume 14 of thecoupled cell culture container 10. The sub-flow area 72 b, which wasalready filled with the medium taken from the culture volume 14 in theprevious sampling process step, has been filled again or remains filledwith the same medium. However, contrary to the previous step, the usednutrient medium discharged through the second counter-coupling formation40 is then conveyed through the valve configuration 86 of the thirdconnection formation 80 by means of the delivery pump 122, connecteddirectly thereto, in the disposal container 118. The remaining valveconfigurations 86 of the first, second, and fourth connection formationas well as the second container valve configuration 54 of the secondcounter-coupling formation 40 and the separating valve configuration 74are in their blocked position in order to prevent any unnecessarywetting of flow paths caused by used nutrient medium.

Before any filling of the cell culture container 10 with fresh nutrientmedium takes place, there is another SIP cleaning process that takesplace, which is shown in FIG. 10. The valve position configuration shownthere corresponds precisely to that in FIG. 7, which serves the samepurpose, and to the description thereof express reference is herebymade.

FIG. 11 shows how the liquid flow paths involved are flushed with freshnutrient medium before the filling of the cell culture container 10 withfresh nutrient medium in order to remove any residue of cleaning fluidstill remaining from the liquid supply interface 62′. To this end, bothcontainer valve configurations 54 are in the blocked position, aspreviously with the SIP cleaning process.

Of the valve configurations of the liquid supply interface 62′, thevalve configuration 86 of the first connection formation 76, theseparating valve configuration 74, and the valve configuration 86 of thethird connection formation are in their outlet position. All other valveconfigurations are in the blocked position. The delivery pumps 22connected at the particular connection formations with open valveconfigurations ensure the passageway of fresh nutrient medium startingfrom the nutrient medium reservoir 116 into the disposal container 118.

FIG. 12 finally shows the process following the previously describedflushing process of filling of the cell culture container 10 with freshnutrient medium. To this end, the first container valve configuration 54of the first counter-coupling formation 38 is adjusted in its outletposition, on one hand, while the second container valve configuration 54of the second counter-coupling formation 40 is in its blocked position.All of the valve configurations on the liquid supply interface 62′ sideare in the blocked position with the exception of the valveconfiguration 86 of the first connection formation 76. Thus, freshnutrient medium can be routed from the nutrient medium reservoir 116through the first connection formation 76, the sub-flow area 72 a, thefirst coupling flow path 44 a, and the first counter-coupling formation38, into the culture volume 14 of the cell culture container 10, bymeans of the delivery pump 122 connected to said first connectionformation 76.

Therefore, only fresh nutrient medium or cleaning fluid always flowsthrough the sub-flow area 72 a. Used nutrient medium or cleaning fluid,on the other hand, only flows through the respective other sub-flow area72 b. The separation of the flow area 72 into the two sub-flow areasprevents used nutrient medium from a previously coupled cell culturecontainer 10 that is still present in residue in a sub-flow area withfresh nutrient medium flowing through it from traveling from there intoa subsequently coupled cell culture container 10. This shows the furtherreduction of the risk of cross-contamination.

A further SIP cleaning process, which is shown in FIG. 13, takes placebefore the attachment of the coupling contact with the still-coupledcell culture container 10, upon the filling of the coupled cell culturecontainer 10 with fresh nutrient medium. The valve positionconfiguration in this case corresponds to that of FIGS. 10 and 7, forunderstandable reasons, because it basically involves one andessentially the same cleaning process.

After a cleaning of the liquid supply interface 62′ and the containervalve configurations involved and the wettable points of thecounter-coupling formations 38 and 40, there is a decoupling of theliquid supply interface 62′ from the cell culture container 10, whichhas been coupled up to that point. This decoupling process is shown inFIG. 14.

FIGS. 15 to 18 show those processes of the method previously shown inFIGS. 6 to 14, which do not exclusively involve the flow of liquid froma reservoir into a container, 118 or 120, via the liquid connectioninterface, without liquid reaching a cell culture container or beingremoved from said container. Such process steps without changing thecoupling or flow state at the coupling contact between the cell culturecontainer and the liquid supply interface are all SIP cleaning steps(SIP process) as well as the flushing of the liquid supply interfacewith nutrient medium (purging media).

FIG. 15 shows the state of the cell culture system with alternative cellculture containers 10′ and alternative liquid supply interface 62″directly after a liquid-transferring coupling contact has beenestablished between the coupling formations of the liquid supplyinterface 62″ and the cell culture container 10′.

The alternative cell culture container 10′ of the cell culture systemaccording to FIGS. 15 to 19 differs from the previously discussed cellculture container 10 only in that it has an additional thirdcounter-coupling formation 40′, in addition to the firstcounter-coupling formation 38 in the second counter-coupling formation40.

Accordingly, the liquid supply interface 62″ additionally has a thirdcoupling formation 66′ in addition to the first coupling formation 64and the second coupling formation 66. The third coupling formation 66′and the third counter-coupling formation 40′ may be advantageouslyformed like the first and the second coupling formation orcounter-coupling formation, respectively, and do not differ from themexcept by the attachment location on the cell culture container 10′ andat the liquid supply interface 62″.

With the coupling process (connect) shown in FIG. 15, all containervalve configurations 54 of the first to third counter-coupling formationare in the blocked position, for understandable reasons, in order toprevent uncontrolled escaping of liquid from the culture volume 14.

All valve configurations, 74 and 86, of the liquid supply interface 62″are also in their blocked position during the coupling process in FIG.15 in order to prevent undesirable escaping of liquid from one of thereservoirs, 114 and 116, or the containers, 118 and 120. In addition,the pumps 122 are preferably switched off.

The SIP cleaning process following the coupling corresponds to that inFIG. 7 (see the previous description) with the proviso that all threecontainer valve configurations 54 of the alternative cell culturecontainer 10′ are in the closed position.

FIG. 16 shows the taking of samples from the coupled alternative cellculture container 10′. The position of the valve configurations, 74 and86, on the liquid supply interface side corresponds precisely to that inFIG. 8. This means the valve configuration 86 of the fourth connectionformation is in the outlet position; all remaining valve configurationsof the valve supply interface 62″ are in their blocked position.

Because the alternative cell culture container 10′ has threecounter-coupling formations 38, 40, and 40′, and preferably the firstcounter-coupling formation 38 is intended to be used for the infeed offresh nutrient medium into the culture volume 14 in the precedingexample, it is furthermore preferable for the second counter-couplingformation 42 to be provided exclusively for the discharge of used liquidfrom the culture volume 14 for the disposal, and the thirdcounter-coupling formation 40′ is exclusively allocated to a randomsampling function with the container valve configuration 54 allocated tothis and the delivery liquid flow path allocated to this. For thisreason, only the third container valve configuration 54 of the thirdcounter-coupling formation 40′ is switched to its outlet position withthe process shown in FIG. 16, while the remaining container valveconfigurations 54 of the cell culture container 10′ are in their blockedposition.

According to the above, with the disposal of used liquid from theculture volume 14 in the disposal container 118 shown in FIG. 17, onlythe second container valve configuration 54 of the second containercounter-coupling formation of 40 is switched to its outlet position,while the first and the third container valve configuration of the firstand the third counter-coupling formation, 38 and 40′, respectively, arein their blocked position. The valve position configuration of the valveconfigurations 74 and 86 of the liquid supply interface 86 correspond tothat in FIG. 9, to which description express reference is hereby made.

Upon the disposal of used liquid from the culture volume 14,particularly used nutrient medium, an SIP cleaning process occurs, whichis not specifically outlined, as in the previous example. Because allcontainer valve configurations 54 are in their blocked position in thisprocess and the valve position configuration of the liquid supplyinterface 62″ corresponds exactly to that in FIG. 10, express referenceis made to the description in FIG. 10 for the following SIP cleaningprocess.

The same thing applies to the flushing process in which any cleaningfluid still remaining in the liquid supply interface is flushed out by afresh nutrient medium. Express reference is made to the description ofprevious FIG. 11 for the process in the previous example, which is alsonot specifically outlined.

FIG. 18 shows the process of introducing fresh nutrient medium into thecell culture volume 14 of the alternative cell culture container 10′.The valve configurations, 74 and 86, on the liquid supply interface sidecorrespond in their valve position configuration to that in FIG. 12, towhich description express reference is hereby made in connection withthe valve position of the valve arrangements on the liquid supplyinterface side and the corresponding pump operation.

On the cell culture container 10′ side, only the first container valveconfiguration 54 of the first counter-coupling formation and 38 is inits outlet position; the two remaining container valve configurationsare in their blocked position.

Regarding the subsequent SIP process step and the decoupling of thevalve supplied interface 62″ from the cell culture container 10′,reference is made to the description in FIGS. 13 and 14, with theproviso that all three container valve configurations 54 of the cellculture container 10′ are in the blocked position during these processsteps. The valve position configuration of the valve configurations, 74and 86, on the liquid supply interface side corresponds to that in FIGS.13 and 14.

As a supplement to that, reference is made to the fact that not only theactually shown separating valve configuration 74 may be present at thealternative liquid supply interface 62″, as shown in FIGS. 15 to 18, butthere may be also a second separating supply interface 74′, which is atthe location indicated by the dashed line in FIG. 18. This secondseparating valve configuration 74′ is always in its outlet position whenan SIP cleaning step or a flushing step is implemented with freshnutrient medium, that is when liquid is to be conveyed from a reservoirto the disposal container. In all remaining process steps, a secondseparating valve configuration 74′ is also preferably in its blockedposition.

FIGS. 19 to 21 shows the previously described cell culture system with afurther modified cell culture container 10″. Said cell culture container10′ has only one single counter-coupling formation 38. Accordingly, thefurther modified liquid supply interface 62′″ has only one singlecoupling formation 64. Because each flow to the cell culture container10″ and from it proceeds through one and the same coupling flow path 44a, a separating valve configuration may but does not have to be omitted.In the example shown in FIGS. 19 to 21, the separating valveconfiguration has been omitted. Otherwise, the liquid supply interface62′″ corresponds to the previously described liquid supply interfaces,62′ and 62″, regarding the connection formations and the valveconfigurations 86 provided there as well as the delivery pumps 122,reservoirs, 114 and 116, connected thereto, as well as containers, 118and 120, the description of which is hereby referenced to explain theembodiment in FIGS. 19 to 21.

FIGS. 19, 20, and 21 only show those process steps of removing liquidfrom the cultural volume 14 and of filling the culture volume 14, inwhich actually liquid flows through the delivery liquid flow path 44 ofthe single counter-coupling formation 38. These are the process steps ofrandom sampling (sampling, FIG. 19), media disposal (media out, FIG.20), and the introduction of fresh nutrient medium into the culturevolume 14 (media in, FIG. 21). In all remaining process steps, thesingle container valve configuration 54 of the single counter-couplingformation 38 is in its blocked position. The valve arrangements 86 ofthe liquid supply interface 62′″ are in the same process steps (see theprocess sequence on the right-hand edge of FIGS. 6 to 21), each in thesame position as the previously described modifications, 62′ and 62″.This also applies to the specifically shown process steps of randomsampling (FIG. 19), media discharge from the cell culture container 10″(FIG. 20), and the introduction of fresh nutrient medium into the cellculture container 10″ (FIG. 21). In this respect, the valve positionconfiguration of the valve configurations 86 of the liquid supplyinterface 62′″ in FIG. 19 correspond to that in FIG. 8 and FIG. 16, thevalve configurations 86 in FIG. 20 correspond to that in FIGS. 9 and 17,and the valve position configuration of valve configurations 86 in FIG.21 correspond to that in FIGS. 12 and 18. Regarding the description inFIGS. 19 to 21, express reference is made to the description of theextensively previously described figures.

Contrary to the previously described embodiments, fluid now flowscontinuously along one and the same delivery liquid flow path andcoupling flow path, regardless of whether fresh nutrient medium isintroduced into the cell culture container 10″, removed from it fordisposal, or removed from it for random sampling.

1. A liquid supply interface for a cell culture system for supplyingcell cultures found in different cell culture containers with a nutrientmedium, wherein the liquid supply interface comprises: a housingdefining a flow area; a first connection formation for theliquid-transferring connection of a first fluid line to the housing; asecond connection formation formed separately from the first for theliquid-transferring connection of a second fluid line with the housing;a third connection formation formed separately from the first two forthe liquid-transferring connection of the housing with a third fluidline; a coupling formation formed separately from the connectionformations, which is formed for the producible and detachableliquid-transferring coupling contact according to the operation, with acorresponding counter-coupling formation of a cell culture container; afirst liquid flow path, which extends between the flow area and thefirst connection formation for introducing a first liquid from theoutside into the flow area; a second liquid flow path, which extendsbetween the flow area and the second connection formation forintroducing a second liquid different from the first from the outsideinto the flow area; a third liquid flow path, which extends between theflow area and the third connection formation for removing a liquid fromthe flow area; and a coupling flow path, which extends between the flowarea and the coupling formation in order to remove a liquid from theflow area and/or to introduce it to said flow area via the couplingformation, wherein the first, the second, and the third liquid flow patheach have a valve configuration, which is completely surrounded—with theexception of the respective liquid flow path—by the housing,incorporated in it, without a continuous signal and/orpower-transferring physical connection surrounded by the valveconfiguration up to the outside of the housing; wherein a controlconfiguration with a signaling means generating an electric and/ormagnetic and/or electromagnetic field is assigned to each valveconfiguration, the field of which acts upon a valve body of the valveconfiguration without contact, wherein each valve configuration can beswitched off via the field, acting upon its valve body, between ablocked position, in which the valve configuration interrupts a liquidflow in the liquid flow path in which it is arranged, and an outletposition in which the valve configuration enables a liquid flow. 2-11.(canceled)
 12. The liquid supply interface according to claim 1, whereinthe following applies to at least one valve configuration: the signalingmeans and the valve body each comprise an electrode for establishing anelectrical field between each other, wherein the valve body interactswith a Piezo electrical actuator of the valve configuration such thatthe electric field brings about a structural change to the Piezoelectrical actuator, which, in turn, brings about an adjustment in thevalve configuration between the blocked position and the outletposition; and/or the signaling means and the valve body comprise amagnet, on one hand, and a ferromagnetic and/or magnetized componentattracting its magnetic field, on the other hand, wherein the magneticfield in effect between the signaling means and the valve body causes ashift in the valve body, which, in turn, causes an adjustment in thevalve configuration between the blocked position and the outletposition; and/or the signaling means comprises a magnet and the valvebody comprises an electrically conducting component inductivelyattracting the magnetic field of the magnet of the signaling means,wherein the magnetic field effective between the signaling means and thevalve body effects an induction in the valve body, which, in turn,causes an adjustment in the valve configuration between the blockedposition and the outlet position; and/or the signaling means comprises atransmitter of electromagnetic waves, such as optical signals or radiosignals, and the valve body comprises a corresponding receiver, whereinthe valve configuration has a power storage unit and an actuator, whichare coupled to one another and to the valve body such that the valvebody controls the actuator fed from the power storage unit for switchingthe valve configuration between the blocked position and the outletposition, depending on the electromagnetic waves received.
 13. Theliquid supply interface according to claim 12, wherein the signalingmeans and the valve body comprise a magnet, on one hand, and aferromagnetic and/or magnetized component attracting its magnetic field,on the other hand, wherein the valve body is a valve body of the valveconfiguration, which can be shifted away from its valve seat and/ortoward said seat for form a sealing contact under the effect of themagnetic field between the signaling means and the valve body.
 14. Theliquid supply interface according to claim 13, wherein the valveconfiguration is pretensioned magnetically in the blocked position andis adjustable into the outlet position by the magnetic field startingfrom the signaling means.
 15. The liquid supply interface according toclaim 14, wherein a valve seat of the valve configuration has apermanent magnetic or ferromagnetic tension component, such that amagnetic tension force is in effect between the tension component andthe valve body, which tensions the valve body at the valve seat forsealing contact.
 16. The liquid supply interface according to claim 15,wherein the valve seat has an elastomer contact component, at which thevalve body is directly positioned in the blocked position of the valveconfiguration, wherein then the magnetic tensioning force in effectbetween the valve body and the tension component is an attracting force.17. The liquid supply interface according to claim 1, wherein thesignaling means comprises a locally shiftable permanent magnet or anelectric magnet. 18-22. (canceled)
 23. The liquid supply interfaceaccording to claim 1, wherein at least one part of the valveconfigurations is adjustable, from the blocked position into the outletposition, in an outlet flow direction along the liquid flow path, inwhich it is arranged, via a predetermined liquid pressure difference;but not in the opposite flow direction.
 24. (canceled)
 25. A cellculture system comprising: at least one cell culture container forcollecting and supplying adherent cells therein, a nutrient mediumreservoir, a cleaning fluid reservoir, and a liquid supply interface,wherein the liquid supply interface comprises: a housing defining a flowarea; a first connection formation for the liquid-transferringconnection of a first fluid line to the housing; a second connectionformation formed separately from the first for the liquid-transferringconnection of a second fluid line with the housing; a third connectionformation formed separately from the first two for theliquid-transferring connection of the housing with a third fluid line; acoupling formation formed separately from the connection formations,which is formed for the producible and detachable liquid-transferringcoupling contact according to the operation, with a correspondingcounter-coupling formation of a cell culture container; a first liquidflow path, which extends between the flow area and the first connectionformation for introducing a first liquid from the outside into the flowarea; a second liquid flow path, which extends between the flow area andthe second connection formation for introducing a second liquiddifferent from the first from the outside into the flow area; a thirdliquid flow path, which extends between the flow area and the thirdconnection formation for removing a liquid from the flow area; and acoupling flow path, which extends between the flow area and the couplingformation in order to remove a liquid from the flow area and/or tointroduce it to said flow area via the coupling formation, wherein thefirst, the second, and the third liquid flow path each have a valveconfiguration, which is completely surrounded—with the exception of therespective liquid flow path—by the housing, incorporated in it, withouta continuous signal- and/or power-transferring physical connectionsurrounded by the valve configuration up to the outside of the housing;wherein a control configuration with a signaling means generating anelectric and/or magnetic and/or electromagnetic field is assigned toeach valve configuration, the field of which acts upon a valve body ofthe valve configuration without contact, wherein each valveconfiguration can be switched off via the field, acting upon its valvebody, between a blocked position, in which the valve configurationinterrupts a liquid flow in the liquid flow path in which it isarranged, and an outlet position in which the valve configurationenables a liquid flow, and wherein: the first connection formationconnects the housing with the nutrient medium reservoir in aliquid-transferring manner and thus the first liquid flow path extendsbetween the flow area and the nutrient medium reservoir; the secondconnection formation connects the housing with the cleaning fluidreservoir in a liquid-transferring manner and thus the second liquidflow path extends between the flow area and the cleaning fluidreservoir; the third connection formation connects the housing with adischarge in a liquid-transferring manner and thus the third liquid flowpath extends between the flow area and the discharge; the couplingformation for coupling contact, which is producible and detachable in aliquid-transferring manner according to the operation, is formed with acounter-coupling formation of the cell culture container; the firstliquid is the nutrient medium; the second liquid is the cleaning fluid;the coupling flow path is formed in order to remove nutrient medium fromthe flow area and supply it to the cell culture container and/or toremove it from said container and introduce it to the flow area via thecoupling formation, in a state coupled with the counter-couplingformation. 26-27. (canceled)
 28. The cell culture system according toclaim 25, wherein, in the flow area, a flow path passes by the valveconfiguration of the first connection formation and optionally by thevalve configuration of the fourth connection formation, from the valveconfiguration of the second connection formation to the valveconfiguration of the third connection formation.
 29. The cell culturesystem according to claim 28, wherein the valve body of the valveconfiguration of the first connection formation and optionally the valvebody of the valve configuration of the fourth connection formationprotrudes at least partially into the flow path from the valveconfiguration of the second connection formation to the valveconfiguration of the third connection formation. 30-31. (canceled) 32.The cell culture system according to claim 25, wherein at least onecounter-coupling formation of the cell culture container has a containervalve configuration.
 33. The cell culture system according to claim 32,wherein the container valve configuration is completely surrounded bythe counter-coupling formation and the housing of the liquid supplyinterface, with the exception of the liquid flow path interfusing thecoupling formation and the counter-coupling formation, without acontinuous signal- and/or power-transferring physical connection fromthe container valve configuration up to the exterior of thecounter-coupling formation and of the housing of the liquid supplyinterface, when coupling contact is established between the couplingformation and the counter-coupling formation.
 34. The liquid supplyinterface according to claim 32, wherein the at least one containervalve configuration can be switched between a blocked position and anoutlet position.
 35. The cell culture system according to claim 32,wherein a flow path, in the flow area, passes by the at least onecontainer valve configuration from the valve configuration of the secondconnection formation to the valve configuration of the third connectionformation when coupling contact is established between the at least onecoupling formation of the liquid supply interface and the at least onecounter-coupling formation of a cell culture container.
 36. The cellculture system according to claim 35, wherein the valve body of the atleast one container valve configuration protrudes at least partiallyinto the flow path from the valve configuration of the second connectionformation to the valve configuration of the third connection formationwhen coupling contact is established between the at least one couplingformation of the liquid supply interface and the at least onecounter-coupling formation of a cell culture container. 37-38.(canceled)
 39. The cell culture system according to claim 25, whereinthe signaling means and the valve body comprise a magnet, on one hand,and a ferromagnetic and/or magnetized component attracting its magneticfield, on the other hand, wherein the valve body is a valve body of thevalve configuration, which can be shifted away from its valve seatand/or toward said seat for form a sealing contact under the effect ofthe magnetic field between the signaling means and the valve body;wherein the valve configuration is pretensioned magnetically in theblocked position and is adjustable into the outlet position by themagnetic field starting from the signaling means; wherein a valve seatof the valve configuration has a permanent magnetic or ferromagnetictension component, such that a magnetic tension force is in effectbetween the tension component and the valve body, which tensions thevalve body at the valve seat for sealing contact; wherein the valve seathas an elastomer contact component, at which the valve body is directlypositioned in the blocked position of the valve configuration, whereinthen the magnetic tensioning force in effect between the valve body andthe tension component is an attracting force; wherein, in at least oneconnection formation, an annular axial end face of the elastomer contactcomponent, as a sealing surface that surrounds the liquid flow pathallocated to the connection formation radially to the exterior, makescontact, deformed, at a counter-sealing surface.
 40. The cell culturesystem according to claim 25, wherein the signaling means and the valvebody comprise a magnet, on one hand, and a ferromagnetic and/ormagnetized component attracting its magnetic field, on the other hand,wherein the valve body is a valve body of the valve configuration, whichcan be shifted away from its valve seat and/or toward said seat for forma sealing contact under the effect of the magnetic field between thesignaling means and the valve body; wherein the valve configuration ispretensioned magnetically in the blocked position and is adjustable intothe outlet position by the magnetic field starting from the signalingmeans; wherein a valve seat of the valve configuration has a permanentmagnetic or ferromagnetic tension component, such that a magnetictension force is in effect between the tension component and the valvebody, which tensions the valve body at the valve seat for sealingcontact; wherein the valve seat has an elastomer contact component, atwhich the valve body is directly positioned in the blocked position ofthe valve configuration, wherein then the magnetic tensioning force ineffect between the valve body and the tension component is an attractingforce; wherein the container valve configuration is formed according toclaim 16, wherein an annular axial end face of the elastomer contactcomponent of the container valve configuration makes contact, deformed,at a counter-sealing surface of the liquid supply interface as thesealing surface surrounding the liquid flow path allocated to thecoupling formation radially to the exterior, when coupling contact isestablished between the at least one coupling formation of the liquidsupply interface and the at least one counter-coupling formation of acell culture container. 41-42. (canceled)
 43. A cell culture containerfor a cell culture system as well as for producible and detachablecoupling contact with a liquid supply interface comprising: a culturevolume including the container body with a fill and/or ventilationopening, through which gas, liquid, paste, and/or solid bodies can befilled into the container body and removed from said container body; andat least one counter-coupling formation formed separately from the filland/or ventilation opening, which is formed for establishing anddetaching a coupling contact with a corresponding coupling formation ofthe liquid supply interface, in which a delivery liquid flow pathextends between the at least one counter-coupling formation and theculture volume, in order to introduce a liquid into the culture volumeand/or to remove liquid from said culture volume via the delivery liquidflow path, wherein the at least one counter-coupling formation has acontainer valve configuration; wherein the container valve configurationcan be switched, between a blocked position, in which the containervalve configuration interrupts a liquid flow in the delivery liquid flowpath, and an outlet position, in which the container valve configurationenables a liquid flow, by a control configuration with a signaling meansgenerating an electric and/or magnetic and/or electromagnetic field, thefield of which acts upon a correspondingly field-sensitive valve body ofthe container valve configuration without contact.
 44. The cell culturecontainer according to claim 43, wherein the fill and/or ventilationopening and the at least one separately formed counter-couplingformation are provided at opposite ends of the cell culture container.45-46. (canceled)
 47. The cell culture container according to claim 43wherein the liquid supply interface comprises: a housing defining a flowarea; a first connection formation for the liquid-transferringconnection of a first fluid line to the housing; a second connectionformation formed separately from the first for the liquid-transferringconnection of a second fluid line with the housing; a third connectionformation formed separately from the first two for theliquid-transferring connection of the housing with a third fluid line; acoupling formation formed separately from the connection formations,which is formed for the producible and detachable liquid-transferringcoupling contact according to the operation, with a correspondingcounter-coupling formation of a cell culture container; a first liquidflow path, which extends between the flow area and the first connectionformation for introducing a first liquid from the outside into the flowarea; a second liquid flow path, which extends between the flow area andthe second connection formation for introducing a second liquiddifferent from the first from the outside into the flow area; a thirdliquid flow path, which extends between the flow area and the thirdconnection formation for removing a liquid from the flow area; and acoupling flow path, which extends between the flow area and the couplingformation in order to remove a liquid from the flow area and/or tointroduce it to said flow area via the coupling formation, wherein thefirst, the second, and the third liquid flow path each have a valveconfiguration, which is completely surrounded—with the exception of therespective liquid flow path—by the housing, incorporated in it, withouta continuous signal- and/or power-transferring physical connectionsurrounded by the valve configuration up to the outside of the housing;wherein a control configuration with a signaling means generating anelectric and/or magnetic and/or electromagnetic field is assigned toeach valve configuration, the field of which acts upon a valve body ofthe valve configuration without contact, wherein each valveconfiguration can be switched off via the field, acting upon its valvebody, between a blocked position, in which the valve configurationinterrupts a liquid flow in the liquid flow path in which it isarranged, and an outlet position in which the valve configurationenables a liquid flow, and wherein: the first connection formationconnects the housing with the nutrient medium reservoir in aliquid-transferring manner and thus the first liquid flow path extendsbetween the flow area and the nutrient medium reservoir; the secondconnection formation connects the housing with the cleaning fluidreservoir in a liquid-transferring manner and thus the second liquidflow path extends between the flow area and the cleaning fluidreservoir; the third connection formation connects the housing with adischarge in a liquid-transferring manner and thus the third liquid flowpath extends between the flow area and the discharge; the couplingformation for coupling contact, which is producible and detachable in aliquid-transferring manner according to the operation, is formed with acounter-coupling formation of the cell culture container; the firstliquid is the nutrient medium; the second liquid is the cleaning fluid;the coupling flow path is formed in order to remove nutrient medium fromthe flow area and supply it to the cell culture container and/or toremove it from said container and introduce it to the flow area via thecoupling formation, in a state coupled with the counter-couplingformation.